Unlocking Everything in the Binding of Isaac (Repenting Update!)

Steam Community guide by Dragonova.

Introduction

Hi, I am a big fan of The Binding of Isaac: Rebirth (I have 719 hours in the game as of writing this) and I tried my best to fully complete this game without the use of any guides or wikis. I actually got pretty far but came to the conclusion that completing this game is too big of a task to do on pure self-discovery alone. Now that I have 1,000,000% (and am on my way to Dead God), I discovered how useful having a guide is to completing this game. I also noticed that most steam guides and wikis are a bit... lacking in terms of offering advice or methods to various unlocks.
In their defense, a good chunk of Isaac's unlocks and their descriptions are really self-explanatory, but not everything is and I can imagine trying to unlock all 637 achievements (or Secrets as I will refer to them) can be really overwhelming for a new player. So I'm going to go over every single Secret and its unlock method listed in the order that Steam lists them. This guide also serves as an achievement guide as every Secret has and achievement and vice versa.
This guide does SPOIL EVERYTHING so explore at your own risk. I attempt to avoid or hide random spoilers in unrelated Secrets, but you should use Ctrl + F (or whatever it is on Mac) to find a specific Secret if that's what you're here for. This guide makes liberal use of grouping various Secrets together so if you cannot find a specific item using Ctrl + F; try searching for it's category (the specific location/boss in question for example).
Words of note before we start though:

• To address the elephant in the room, this guide is NOT fully updated for Repentance. I will be updating the guide periodically with some more important Repentance stuff, but don't expect a total overhaul on this guide for a fair bit of time. That being said, the vast majority of Afterbirth+ Secrets translated to Repentance pretty directly.
• Isaac is a fantastic game but getting to 110%, let alone 1,000,000% or getting to Dead God, is not for the faint of heart and requires a large amount of time commitment. Even with the guide, I could still foresee fully completing Isaac taking an inexperienced player anywhere from 250-300 hours of playtime. Unless you are dedicated, I would just stick to the various Endings, Completion Marks, and consider Platinum God your completion goal.
• You should try to play in Hard or Greedier Mode pretty much 100% of the time if you're in hardcore completion mode! There are many, many Secrets tied directly to doing everything in Hard Mode. The difficulty curve that comes with playing only on the harder modes is rough (and optional), but it can save you much pain in the future as Isaac already takes a long time to complete.
• Go into your options and turn on the Found HUD and Extra HUD. These are extra display elements that show you your current stats and recently picked up items. Both of these are massively helpful throughout your runs. There's also some other helpful options in that menu, but these two are the most important.
• I won't act like this guide does the best job at explaining every facet of The Binding of Isaac. There are much better places for general information on the game such as
  the wiki[bindingofisaacrebirth.gamepedia.com] or other steam guides I wish I knew about prior to completing this game. My personal favorite being The Bindening™ (link below). As for myself, I am just throwing my own hat in and not attempting to be the "new definitive Isaac guide" or anything like that.
  https://steamcommunity.com/sharedfiles/filedetails/?id=1441000071

Prologue: Keywords

Feel free to skip this if you know how to play, but there are some keywords I use throughout the guide that should be explained ahead of time just so you know what the hell I'm talking about (assuming you are brand new to the game). These words will usually be capitalized despite not being a name or specific item, enemy, etc. If a keyword is not capitalized later on then that's probably a mistake, my bad.
Secret - Another word for achievement. Unlocking literally any achievement in Isaac will put a piece of paper to the screen saying what you unlocked. I assume the game calls these Secrets because said piece of paper refuses to tell you how you unlocked it.
Completion Secret - These have their own section at the ending of the guide because they are Secrets that unlock nothing and merely demonstrate your mastery and/or completion of the game.
Ending - There are 23 Endings in the game, but you'll get every single one of them in the process of finishing even a single Character's Completion Marks so it's not too big of a deal.
Floor - The level you are currently on. There is usually 2 Floors per Chapter until you reach Chapter V, at which then Floor count does not really matter anymore. For example, Chapter III could also be called Floor 5 & 6 while Chapter V can be any variety of Floors.
Chapter - There are 6 main Chapters in the game which you progressively unlock as I will explain in Part 1.
Alternate Floor - Chapters I - IV can gain alternate forms such as Basement becoming either the Cellar, Burning Basement, or Downpour/Dross. They provide a new coat of paint with different enemies and bosses.
Character - It's you and who you decide to play as when you start a run.
Completion Mark - Each Character has a little paper on their Character selection screens and when you pause. As you beat certain bosses or complete specific tasks, you'll unlock Secrets which are displayed in the little paper. I will explain how to get each of these in the rest of the guide, but in case you want to know now, the symbols are as such (from top-left to bottom-right).
Heart = Mom's Heart or It Lives!, Cross = Isaac, Star = Boss Rush, Upside-down Cross = Satan, Photo = ???, Inverted Photo = The Lamb, Brimstone = Mega Satan, Cent = Ultra Greed, Tears(?) = Hush, Tearing of the Paper = Delirium, Knife = Mother, Note = Beast. Any of these symbols being in blood means you've done it in Hard Mode and this is important because there is a Secret for doing all of a Character's Completion Marks in Hard Mode.
Hard Mode - Selected when you choose your Character, this mode makes special multicolored versions of enemies and bosses called champions more frequent, makes curses MUCH more frequent, reduces heart drops, causes Shops to have less items, and so on.
Greed/Greedier Mode - Selected when you choose your Character and operates completely different from the base game of Isaac. The idea is that you fight waves of enemies and then bosses to earn money. Money is then spent in a constantly restocking super shop. Greedier is the Hard Mode of Greed and must first be unlocked by the Greed Donation Machine.
Boss Room/Treasure Room/Shop - Three rooms that all spawn throughout a normal game and serve distinct purposes. There are tons of special rooms in the game, but these are the most important:

• Boss Rooms are where you fight a boss and how you progress onto the next Floor. Bosses are determined by the Chapter you are on and are predetermined at the end of Chapter III, Chapter IV, and then every boss after. At the end of any boss in Chapters I - IV, you receive an item (usually a stat up one).
• Treasure Rooms are rooms that locked on every Floor other than the first one. Treasure rooms only show up for Chapters I - III and grant free items that are usually more powerful than what you get from Shops or Boss Rooms, but are consequently more varied and not usually just stat ups.
• Shops are the main way you spend coins. They have pickups and Shop-specific items for sale. Items in the Shop can have their prices randomly become red, which means they are on a 50% sale. Shops also contain the Donation Machine described below.
  Devil Deal/Devil Deal Room - Devil Deal Rooms can be found as early as Floor 2 and normally have a high chance (85% - 100%) to show up after the boss is killed. In there, you can buy items in exchange for losing max health. Chances for these rooms can also be raised slightly by certain actions. Devil Deal Rooms will stop showing after Chapter IV. Devil Deal Chance drops by roughly 40% each under these two conditions. The two conditions are:
• You take "red heart" damage in the current room you are in. Note that soul hearts, black hearts, and any other form of health are not included in this and can be used to shield your Devil Deal chances.
• You take "red heart" damage at any point on the Floor. This effectively means that taking "red heart" damage your first time in the Boss Room will plummet your Devil Deal chances to almost single digits.
  Angel Room - If you fulfill the conditions to get a Devil Deal Room and then ignore it you will get a chance to get an Angel Room. Afterwards, when a Devil Deal appears on a following Floor, you will get an Angel Room instead. Angel Rooms give their own special items and they are completely free to boot, but are arguably not as good as Devil Deal items.
  Secret Room - There are 1-2 of these rooms on every Floor and are found by bombing the middles of walls. These rooms can have enemies, items, coins, or literally nothing. Secret Rooms need to be connected by at least 2 other rooms and none of the rooms connected can have objects or gaps in the way. There are also Super Secret Rooms that are never connected to any room and are usually off in some random corner or near the Boss Room. Neither type of Secret Room can ever be connected to a Boss Room.
  Planetariums - After being unlocked, these are incredibly rare rooms with special items that cannot be found elsewhere. Your chance to get a Planetarium is initially 1% and if spawned, they'll be a separate room like a Treasure Room needing a key. There are a few items that increase Planetarium chance, but the biggest way is to not enter Treasure Rooms at all. This increases Planetarium chance heavily.
  Donations Machine - There are 2 of these in the game, one in normal Shops and another at the end of Greed Mode. Many Secrets are tied to the filling of both of these up to 1,000 coins.
  Challenge - While on the main menu, you may notice the Challenges menu. I'm making a section at the end for describing how to unlock and beat every Challenge because unlocking a Challenge and the item you unlock for beating it both count as Secrets.
  Transformation - There are ways to upgrade your Character in a run beyond just items and pickups. The most notable way is a Transformation. Upon picking up a series of (usually 3) items or effects, you gain a permanent upgrade for free. These items or effects typically have a theme (Guppy, Mushroom, Flies, etc) and are needed for some Secrets.

Part 1: Unlocking Floors (1/2)

I know I said I would keep everything to the order that Steam lists the Secrets, but I am making a few exceptions to this. These being Completion Secrets, Challenges, Floors, and Character Secrets. These need their own sections in order to make this guide even slightly cohesive.
I'll start with Floors & Characters as these are the first things you should focus on while playing through The Binding of Isaac. I don't recommend seeking out any other kind of Secrets until Floor & Character Secrets are done. Chances are you will unlock some things before all of the Floor & Character Secrets are done, but it's impossible to do most things without these Secrets first.
The Womb
Chapter 4 - The Womb unlocked.
When you first play The Binding of Isaac: Rebirth you will only need to make it through the first 3 Chapters. The boss of the Depths II will ALWAYS be Mom and defeating her gives you your first Ending and unlocks Chapter IV for subsequent runs. You take full heart damage from everything at Chapter IV onwards.
It Lives!
You're future's past awaits.
After unlocking The Womb, you'll be able to make it all the way to Womb II where the boss will (much like Mom) always be Mom's Heart. Each time you beat it, you'll get a new Ending and Secret up to 11 times. After the 11th time, Mom's Heart will permanently transform into It Lives!. Beating it allows you to progress to either of Chapter V Floors. The transformation to It Lives! does not change any Completion Marks or Secrets related to defeating Mom's Heart outside of making them slightly harder.
The Polaroid & The Negative
Unlocked new items.
These 2 items are unlocked by beating the boss for The Cathedral and Sheol 5 times each respectively. When either The Polaroid or Negative are unlocked, they will appear as the boss reward for defeating Mom instead of a generic item. You then can choose one and only one. Opening the chest that spawns after completing The Cathedral with The Polaroid in hand will take you to Chapter VI: Chest. The same thing can be done with The Negative and Sheol's chest, which will take you to a different Chapter VI: Dark Room. Having the wrong one of these items for their respective chest will end your run right then and there. Both of these items also actually have powerful effects so it's worth it to pick carefully even if you're not aiming for either Chapter VI.
Angels
They are waiting.
As soon as you get to either Chapter VI Floors, you may notice a giant, locked golden door that isn't needed to fight the boss of the Chest or Dark Room. Upon clearing either Chapter VI, you will get the "Angels" Secret, which unlocks 2 hidden boss fights. If you bomb or explode the angel statue in any Angel Room, you will start a fight with either Uriel or Gabriel as a boss. You may have fought the Angels before getting this Secret via Boss Rush. Each one will drop a Key Piece upon death in an Angel Room. If you kill both of them you will form a complete key that can be used to unlock the golden door in Chapter VI where you then fight the true final boss... of Rebirth that is.
Boss Rush
Not a Secret.
The Boss Rush is an optional fight you can take on for a Completion Mark. You access the Boss Rush by defeating Mom in under 20 minutes, at which then a hole will open up in her boss fight arena. Here, you can choose a free item out of a few choices and then will fight 15 waves of bosses from Chapters I to IV. This is very challenging and requires a lot of preparation so be wary. You can always check your current time in your run by pressing TAB on the keyboard.
Blue Womb
Unlocked a Hidden Chapter.
After you've beaten Mom's Heart 10 times, you must beat her or It Lives! in under 30 minutes. Then you'll be able to access a new Floor. Much like with Boss Rush, a hole opens in the arena that takes you to a new Floor known as ??? or the Blue Womb. You will get 2 Treasure Rooms, 4 gold chests, and a Shop, and trust me... you'll need it.
New Area, Delirious, and Lil' Delirium
Unlocked a new area.
Completing the above area once will give you a new Ending. After that, clearing it gives a 100% chance to find a Void Portal in a room above the boss arena. ???, The Lamb, and Mega Satan also grant guaranteed Void Portals, and other endgame bosses have random chances for it. Going through the Void Portal will take you to The Void, a massive Floor with many Boss Rooms containing bosses. One of these Boss Rooms, at random, has a chance to be the true endgame boss for Afterbirth+. Defeat this brutal boss fight and you will unlock the Delirious Secret as well as Lil' Delirium.
A Secret Exit
Complete ??? 3 times.
Once you've completed the Blue Womb 3 times, you'll unlock a strange door that appears at the end of any Floor in Chapters I - III. These rooms will take you to a set of Alternate Floors with entirely new enemies, mechanics, and bosses that are more difficult than the regular Floors.
The door in Chapter I requires a key and will take you to the Downpour. The door in Chapter II requires 2 bombs and will take you to the Mines. The door in Chapter III will deal 2 full hearts of damage to you and can kill you. This one takes you to the Mausoleum. Swapping between this alternate path and the main path will advance the Floors faster than usual.
For example: Leaving from Downpour I to the main path will put you in Caves I.

Part 1: Unlocking Floors (2/2)

The Corpse and Rotten Hearts
Enter the Corpse...
In Chapter I: Downpour, there will be a room with a mirror and a special indestructible white fire. If you touch the fire, you will temporarily become The Lost and can go through the mirror. Bombing the mirror destroys it forever. When in the mirror world, you will need to make your way to the Treasure Room where you will pick up Knife Piece 1.
In Chapter II: Mines, if you have the first Knife Piece, you will find these yellow floors buttons that you can step on. A special room will have a mine cart that needs are 3 buttons to be pressed. Once you do, you can enter the mine cart and go to a special tunnel where all of your items but what you started with are gone. At the end of this tunnel is Knife Piece 2, but be careful. Once you pick up the piece, a monster called Mother's Shadow will begin to chase you. She does a full heart of damage and moves slowly but occasionally charges with an audio cue. The tunnel will be filled with all sorts of puzzles and traps that you must navigate while continuously dodging the Shadow. A tip for this is that Mother's Shadow moves back a bit before charging so it's okay to stand still and just move slightly after she begins the charge in order to escape a tight spot.
Lastly, in Chapter III: Mausoleum, you will fight an alternate, harder Mom fight. If you have the full knife after defeating her, you'll see a flesh door that you must shoot the knife into the door. You will then fight a harder version of Mom's Heart with new patterns (note that this isn't It Lives!). If you do kill her heart, the room will grow dark and you'll be able to enter Chapter IV: The Corpse. This area operates like The Womb, no Treasure Rooms and all, but has entirely new enemies and bosses. At the end of the Corpse is a nightmarish fight that counts as a Character Completion Mark.
A Strange Door
Where could it lead to?
Once you defeat the boss of the above area, you will unlock this Secret. Now at the end of specifically only the main path Chapter III's second Floor, you can find an odd-looking door. Complete the floor as normally, but look for a skull with an "x" on it. Blow this skull up and you'll get a The Fool tarot card. DO NOT USE IT until you fight Mom. Then, after defeating her, grab either The Polaroid or The Negative and use The Fool to avoid being trapped in her arena (any other method of teleportation also works here). Go to this odd-looking door and touch it to put either The Polaroid or The Negative into the door to open it.
After this, you'll enter Mausoleum II and complete it as usual. However, instead of there being a boss, you will be forced to pick up Dad's Note. This instantly begins the Ascent. The Ascent will have you go through smaller versions of the Floors you already completed in reverse order. You start at the Boss Room and must head to the starting room. The Boss Room and Treasure Rooms are preserved from earlier (use this to cheese Planetariums), but otherwise all rooms are different. As you ascend higher, you will come across Tainted enemies, which are new versions of easier enemies that are boss-levels of difficult. You take full heart damage in the Ascent and get few items so be careful.
Note: The section after this is so damn cool that I beg you to stop reading now and come back here after you've done it once yourself. I DO NOT want be the one who ruins this for you.
Once you've reached Basement I and ascend from there, you'll go... Home. Home is a preset Floor with a few pickups, a chest, and a box in Mom's Room that gives you items. If you sleep on Mom's Bed, it'll become night and the TV in the Living Room is on. Gaze into the TV and you will begin The Final Chapter, a series of MANY boss fights that all result in a Character Completion