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This is a "Wild Mass Guess" entry, where we pull out all the sanity stops on theorizing. The regular entry on this topic is elsewhere. Please see this programme note.
The Binding of Isaac
Isaac's basement is one of many portals to hell
These portals lure in lost souls by slowly driving them mad with the compulsion to slaughter their loved ones and each other. That's why Isaac's mother started hearing commands from "God" to murder her son. The corruption drives people to use painful self-mutilating power-ups to increase their ability to hurt one another. The enemies you fight were once normal human beings (many of which were other children). Hence, Isaac's mother is human in the intro but transforms herself into an Eldritch Abomination by the time you fight her. Children's tears and human blood injure these tainted beings, but that fact only drives them to weaponize their last vestiges of humanity.

Isaac's gestation irrevocably damaged his mother. All subsequent pregnancies resulted in miscarriages.
That's why Mom tried to dress Isaac as the daughter she always wanted, that's why she became so tormented and neglected Isaac like he was a curse, that's why Isaac's father left.

Neglected, Isaac slowly starts to understand that his mother rues his existence. It's why Isaac's imaginary ventures are tormented by visions of himself, killing his half-formed and broken potential siblings and eventually tearing through his mother's internals. It's why Isaac wishes so badly that he could destroy himself in the womb, before he destroyed her. His imaginings are all recorded in the form of his drawings ("I was killed by...").

When he sees his mother finding solace from her grief in her faith, he flips open a Bible. He's terrified. "This kid is called Isaac! I bet Mom wants me dead too!" Gameplay is a psychonautical mental battle, for Isaac's belief in his right to exist. The different playable characters are his different personality facets, Satan is his sins, Isaac 2 is his resulting regret at existing (that's why "II"ssac looks so happy when he dies), and ??? is his subsequent suicidal urges.

When he tries to suffocate himself at the end of the game, he's not trying to escape. He's trying to ease his mother's suffering, to stop her from being constantly reminded that she's barren, and that she subjected so many sentient fetii to horrible deaths. He wants to be forgotten.

The polaroids, memories of a time before the complications, flash before his fading eyes. The ending is a deliberate cliffhanger. Will he conquer his fears and open the box again? It's down to you, tropers.

  • As an astute fellow further down pointed out, "Sister Maggy" later turns up as a floating stillborn fetus. I cite that as supporting evidence.
  • "Psychonautical?"

Larry, Jr is a successful experiment of a human centipede
This boss has a kind of similar behavior to the Centipede, and he (or rather they) shits everywhere while you fight him, thus the WMG. Well, if he isn't human now, he might have been at some point.
  • Also, try looking carefully at his head. He's crying.
  • Sometimes when you shoot the body, Larry Jr. splits into two. Now, where would the other head come from? From the body. It's not separate segments. These are actual heads connected into a centipede.
  • This is supported by the "buttlicker" enemies, each separate heads connected into a chain, and who are most likely in the process of becoming a Larry Jr.

??? is suicide incarnate.
Isaac clearly has some thoughts of suicide, wanting to destroy his unborn self, shutting himself in the toybox, and all that. Maybe ??? is a possible-future dead Isaac — that's irrelevant. In-game, ??? is incredibly weak, has no capacity to heal, and a tendency to draw flies. He's suicidal for the player.

The amount of health that Isaac's persona has is related to how comfortable he is with that side of him.
??? is something he's horrified about, his emo (Eve) and rebellious (Judas) sides are ones he doesn't like, being strong and brave (Cain) is something he doesn't have the confidence for. His normal self is okay... But Magdeline is what he feels most comfortable with, hence the higher HP.
  • Makes sense. He also simply can't relate to Sampson, who is the side that has a sense of anger and justice, a side he can't express under Mom. He feels most comfortable as a defensive, nurturing personality with Maggie's low speed and Yum Heart.

Satan represents Isaac's father.
When you finally fight Satan, he opens the battle with a distorted, demonic vocalization. Upon further examination, this is actually Mom's "Isaac!" line, just reversed and deepened. How does The Devil know your name? See title of WMG. In Isaac's mind, Satan represents his father. Dad's Key makes it clear that Isaac's father left their family. Isaac's mother presumably demonized her former husband, causing Isaac to hate him and apply a sort of "ultimate evil" tag to him. Now, Isaac's mother, being extremely religious, would obviously also apply the same tag to Satan, causing Isaac to link the two together in his consciousness.

God never demanded a sacrifice. Isaac's mother was having delusions.
Some analyzers of the original Christian myth say that God stopped Abraham's hand when he was about to kill Isaac because God had never asked for a sacrifice, and Abraham was just imagining things. Following that line of thought, perhaps Isaac's mother in the game was also the same way. This would certainly explain why God stops Isaac's mother even though he asked her to do all those horrible things to Isaac. There were never such orders. Isaac's mother just went crazy from watching so much Christian TV.
  • Given the Halloween Update, she might have been manipulated by Satan.
  • Either that, or it's supposed to mirror the story as it is — God asked her as a test of faith. The reason He stopped her so violently was because she showed no remorse in killing her son, which showed she had faith in Him but no compassion for fellow humans.

The 11th Ending is a Time Loop from Future Isaac to be later found by his younger self in the 10th Ending
Thus making sure that its younger self will wake up from the illusion of salvation from his mother by the bible that God used or that he was making any progress at all by going on and on with killing his mother in self defense. In the end, he will realize that there is only death as a escape from the inevitable sacrifice by the hand of his mom, and God would not save him either.
  • This is sort of supported by the fact that XXX has the same nightmares as all the other characters, and that Mom still calls him 'Isaac'.

Isaac is an aborted fetus
His mother heard the Voice of God when she was pregnant, and sacrificed her unborn child. She's later been plagued by delusions of what she's done and what happened to him and where he is now, and the game is made up of her hallucinations.
  • Supported by The Wire, It Lives: Your Past and Future Self, and the 11th Ending.

Almost every enemy is a possible Bad Future for Isaac
Many items end up making Isaac look like certain enemies. Or, alternatives, many enemies look like Isaac with certain items. The Seven Deadly Sins is where it's the most obvious, and with a few items from the Devil Room, he begins to strongly resemble The Fallen as well. Assuming the above WMGs are true, why stop there?

Isaac is an abused, unwanted child, and/or the spawn of Satan — Either way, he wants to return to the womb and start over
He's naked. He has no possessions. His weapons are all body fluids. Most enemies resemble Isaac. "It Lives" IS Isaac as a fetus. Every form of Isaac is him dressed as a potential version of Isaac in the future. XXX/??? the Dead Baby — to whom Isaac reacts in absolute horror — is obtained AFTER YOU KILL ISAAC'S FETUS FORM. Every power-up mutates Isaac as well, representing future versions of him.

If we assume he's the spawn of Satan, it explains the offers and why he fights him at the end — it's a battle for control over his destiny.

In the end, Isaac has a showdown with Satan and finds a final chest... which cycles through all the personas he has taken and returns him to his room. What's in the chest, the same sort of chest that's found in the Womb? A chance to start over — Isaac can either keep his current life or try a new one (he chooses the latter).

Forget "Bad Future" — Isaac doesn't even want his Bad Present.
  • Isaac being the spawn of Satan, or some other kind of demon, is supported by the ending unlocked by beating the Cathedral. You fight Isaac himself, and the ending is Isaac looking into the mirror and seeing a pitch-black demonic version of himself.

Isaac's mother abuses him and takes away his clothes because he crossdresses.
Either the "voice of God" thing was made up entirely, or her disturbed mind created it as a justification for extreme measures to prevent her child from being "deviant". Once she saw that he was still managing to jerry-rig costumes together, she decided the only way to stop him was to kill him outright.

Everything you play is Isaac's imagination.

Warning: Unmarked spoilers.

Okay, so, Isaac's mother does take away his toys and later thinks she has to kill him. He runs away in the basement and, while his mother is chasing him, hides in a chest and starts imagining things to pass time. However, because he lost his toys and his mother wants to kill him, Isaac can't think of anything happy, so his imagination (in other words, the game) is filled with his interpretations of all the nasty stuff he overheard from his mother's christian broadcasts (or he is just a weird child, believe in what you want to believe). The unlockable characters are all imaginary friends he makes up for the fantasy as he plays, and so are the unlockable items.

The part when you beat Mom for the first time in the game is actually her closing in on him and searching for him. Then, the bible falls on her head, but that does not kill her. Rather, it knocks some sense in her head, and a The End... Or Is It? ending is actually just made unnecessarily ominous. Isaac's mom actually apologizes to him.

The ten mom kills that follow in the game is her returning Isaac's toys to him. However, he finds the imagination game to be a lot more fun than his toys were, so rather than playing with the toys, he uses them as an inspiration for some new elements for his fantasy. The final ending shows Isaac just returning to do what he did before: imagine.

Hey, does everything here have to be as grimdark as the game itself?

EDIT: Now that the Wrath of the Lamb is out, I guess I have to update this.

Isaac is growing up. He is getting now types of toys, new ideas, and is slowly nearing puberty. I say this because the items and bosses seem to be a bit more "mature" and different (see: puberty pills, stem cells, those faces + hearts, stuff generally not related to Bible, new rules, new floors, et cetera.) However, he realizes that he can beat all the bosses he thinks up, so he makes himself a new boss, the only one that might have a chance to defeat him: himself.

After Isaac does that, he tries to find new ideas and begins to realize that he is slowly outgrowing his game. He sees his devil form in the mirror as a lot more awesome form of him that, well, he just won't be able to be like anymore. That kinda correlates to the person playing the game realizing that he/she is running out of things to do.

Alternatively, Isaac is beginning to understand just how twisted some of the stuff he made up is.

Whatever it is, the final level, the Chest, is Isaac melding reality with imagination, giving himself the greatest, final challenge: Leaving his imagination game behind.

  • Including the toy he uses to hang himself?
    • Considering what monsters he made up, something like that is kinda par for the course.
    • I desperately want this to be true. I really do.
  • Perhaps Isaac is so obsessed with the imagination game that he starts spending all his time in the chest and begins to ignore the real world and his basic needs for survival. The Dead Baby is a warning from his mind that if he doesn't stop soon, he'll end up like it.
    • Wouldn't that explain neatly why all the rooms you explore all have the exact same shape as the chest?

To go with the above, Satan in-game is actually Isaac's dad
Basically, in Ending 13, we can see that Isaac's Dad left the family, and beforehand we see a lot of sad Isaac, so clearly there was a messy divorce, causing Mom to go mad from despair. Therefore, in Isaac's imagination, the only one that could cause such suffering is the devil.

First ending is the real ending.

This is similar to the above theory: As we can see, Isaac drew the opening narration pictures and the "Bible kills Mom" ending on the paper. The intro was Isaac recapping to himself what was happening, the actual game was hallucinations/imagination, and in the end he imagines himself a happy ending and draws it. But since it's imagination, that doesn't really kill Mom and she comes to the basement.

If/when the expansion is released, the Final Final Final FINAL boss will be God Almighty.
Averted, actually. YOU are the final boss!

Issac has superhuman abilities, and when he grows up, he will become almost invincible. The family were mostly threatened by the mother's state.
Issac, from birth, had to endure hardships. His mother's womb is REALLY messed up. If he came out of that, alive, he has to be tough. After that, his father probably got sick as all hell. Possibly nymphomaniac of the millina to keep that up. Most kids were broken before they even fully formed, leaving us the eyeless (taken out before they could fully form their eyes), headless (got so nasty a cranial infection that it had to be removed), and then genetic issues (the fly hives and the like being unable to physically take care of themselves). Issac was so tough that he was able to resist all the problems, and his genetics were sound. Because he had to go through what is basically a warrior's challenge at birth, he was so much tougher for that, but because of that, he was too awkward around other kids because he never wanted to interact physically, so they teased him.

Isaac is the Anti Christ, and the game is a Batman Gambit from God to make him into an Anti Anti Christ.
This may or may not tie in with the "in his imagination" theory, i.e. it might be images, dreams, or hallucinations sent to Isaac from God. Specifically, by enduring the horrors of his mother's excessive fundamentalism, he will be protected from becoming a Knight Templar when he discovers his powers; at the same time, fighting the monsters in the dungeon (and eventually Satan himself) both physically and spiritually gives him the means to fend off those who would do him harm, man or demon. Once he finally triumphs over Satan, God either erases the events from reality and makes them as nothing but a daydream (the memory of which will nonetheless keep Isaac strong in the years to come), or makes the dreams/images stop plaguing him so he can rest.
  • Supported by the ending unlocked by beating The Cathedral at the end of Wrath of the Lamb. You fight Isaac himself, and the ending is Isaac looking into the mirror and seeing a pitch-black demonic version of himself.
  • Note also that as of Wrath of the Lamb, The Devil Room will occasionally be replaced by an Angel Room. Perhaps God has decided that He needs to reach out to Isaac more, to ensure his success?
    • The boss fights in the Cathedral and Chest do lend some credibility to this. Throughout the fight, Isaac and XXX are being actively empowered by heavenly forces. And when you knock him down to 1/3rd heath and he gets angelic wings, he's smiling. It does seem to say that Isaac is, at heart, still a good kid.

EVERYTHING is in Isaac's imagination, even his mother trying to kill him. His mother's been dead all along.
Perhaps Isaac's mother dies in her chair while watching her Christian shows, and the trauma of either seeing her die or finding her corpse drives Isaac crazy. Add in whatever madness that was being broadcast on the TV, and all those things combined would probably be enough to cause a little kid to snap.

Isaac's mother removed his penis.
His penis is visible in flashbacks, but not during the game. At some point before the voice's third declaration, Isaac's mother thought of another way to help free Isaac from sin.

The basement under Isaac's house, for some reason, is Hell
Kind of an obvious one, with all the aborted/stillborn/mutated/whatever siblings all over the place. Nothing here dies.

It's all in Mom's imagination.
Whether by miscarriage or abortion or accident or murder, Isaac is dead. Mom creates the events of the game within her head, starting with God's commandment that Isaac should be killed, to rationalize Isaac's death. Her fears tell her Isaac has fallen into Hell; her self-blame and self-loathing place her as a monstrous enemy of Isaac.

Itīs all a Xanatos Gambit of Satan
Mom never heard Godīs voice. It was Satan, who tried to corrupt someone. The possible outcomes: -Mom kills Isaac, corrupting her soul.
-Isaac kills Mom, probably having collected enough "Devil-Items" to be corrupted
-A monster kills Isaac, Satan can try the same with another family
And Isaac battling the final boss is because he found out about that gambit and is seeking revenge.

Envyīs and Prideīs names are swapped.
Just think about it: Envy just floats around, smiling and being proud enough to not even attack, while Pride spawns bombs and energy-ray-things, generally being destructive, because heīs probably envious of what others have and wants to destroy it.
  • Actually, their names do make some sense. Envy splits into multiple enemies, and it is the only sin that can't truly be done by a single person. Pride, on the other hand, seems pretty confident for a boss who can only attack by either spamming bombs, which almost certainly involves hurting himself, or a diagonal attack, which no sane person would get in the line of fire for, as you can only fire in the cardinal directions.
  • Envy and Pride are Stealth Puns like Sloth being a lazy palette swap: he's beside himself with envy, and he's radiant (diagonal beams)/bursting (troll bombs) with pride.

Mom is simply getting a second child
When his Mom gets pregnant, he thinks she wonīt pay attention to him anymore, thus the taking of his stuff. He begins to feel unwanted, believing his mother wants to get rid of him and tries to abort the fetus himself (It Lives!), even succeeding in his task. Then he realises that heīd love having a new brother or sister and thinks, the dead baby would be alive. It would even explain the overabundance of dead babies in the basement!

His mother wants to kill Isaac because of the father.
Note that the opening narration specifically states that Isaac lives alone with his mother, with no father to be found (and, indeed, a father would presumably attempt to defend him). With his mother's strong Christian roots, a divorce seems unlikely, which leaves two likely scenarios:
  • Isaac is a product of rape, and his mother goes insane and attempts to "protect him from sin" because she goes insane with the fear that he might turn out like his father,
  • Or Isaac's father and mother truly loved one another, and his father's death led to his mother going mad from despair.
    • The latter could indeed be possible, if this picture unlocked by beating Wrath of the Lamb with all 6 characters is any indication.
    • Ending 13 shows that his father left the family.

The dead corpse in the shops is really Greed.
They have the exact same skin tone, Greed wears the noose cut off... It's like he watched you descend from the Basement to the Depths, where he may fight Isaac out of spite. Note, Depths 2 is the last level for a shop, and that tends to get replaced by Greed. The Womb and Sheol don't have shops. Probably tried to pull a You Have Outlived Your Usefulness on a potentially overpowered kid?

Isaac's Mom isn't religious at all.
The intro story and first ending are apparantly narrated by Isaac inside his head, as each of them are his own drawings, and yet they are filled with religious themes and his mother's chanting (note that when she talks ingame, her voice is different, and she only says 'Isaac'), along with the bible killing her. Not only that, but there are many indications of child cruelty ingame ('Dinner' being Dog Food, as an example) which shows that his Mother has been deranged and abusive for a long time before her psychotic episode, despite the intro describing their lives beforehand as 'happy'. The religious themes are there because Isaac himself is religious (as people in desperate situations, such as an abusive childhood, tend to be) and the links to the Binding of Isaac story are just his naive attempts to justify his deranged psychopath of a parent. Mom bursting into the room in the 1st ending is just a stinger and not a genuine event, so the 1st ending leads straight into the 11th, where Isaac himself does the only thing he can think of to get away from her and locks himself in the chest, suffocating or starving to death. The game is his confused and terrified attempt to put everything together and remember his life as he waits inside the chest, hence the muddled religious themes and references to an abusive childhood in almost every aspect of the game.

Everything actually turned out fine in the first ending.
In the latest trailer for Wrath Of the Lamb, Isaac's letter to Guppy states that the basement is "different". This implies that he has been there multiple times. Perhaps Mom didn't actually intend on killing Isaac at the end of the first ending? For all we know, she knows Isaac's been to the basement and was offering the knife to him in case he went again?

Basically, ever since then he's been making frequent excursions to the Basement and beyond. But why does he keep fighting his mother, you may ask? Well, that leads to my second WMG...

"Mom" isn't actually Mom at all!
It's a demon taking her form! Basically, Mom wasn't going crazy at all. Instead, a demon had captured her and disguised itself as her. It used Religious Fervor as an attempt to get Isaac to forsake it. And even if he didn't, there was still a chance of murdering a small child and possibly his mother. So, essentially, after Isaac fights the demon, his mother is freed, and she finds Isaac in his room, drawing his adventure down to preserve the memory of it. However, the knife was meant to attack the demon since she thought it was still around.

The demon keeps coming back, resulting in Isaac continuously going into the basement to fight it again and again. Eventually, he heads to Sheol to fight Satan, realizing he needs to destroy the demon at the source. The treasure chest Isaac entered at the end was actually the only way to escape, as opposed to Isaac essentially committing suicide.

Now why would I make these 2 WMGs, you ask? Because Dammit, this story is just too fucking depressing.

Isaac's mother never tried to kill him, it's all made up by resentful Isaac
Mother does think Isaac has been "corrupted by sin" — because she saw the things he's been drawing, those macabre scenes (seriously, have a look at the pause menu) and monster designs. Immediately, she takes away his toys, which surely are to blame for Isaac's behavior. She has him read the bible instead.

Isaac is not easily placated. Inspired by the bible, he makes up several characters to play with. When he encounters the story of Isaac, whose name he shares, he starts imagining a story in which his mother wants to sacrifice him, but he escapes, regains things he used to play with before his mother took them away (and other things he thought that were cool), and defeats her with them. Since he's just a little boy, the plot is simplistic and somewhat nonsensical, but there are cool monsters and stuff!

He finishes the story, but still is bored, so he continues, not caring about the plot at all but just making up new cool items. Things also get a little Freudian...

At one point, he decides it's so fun, he might as well throw in him defeating Satan.

It is all a game... stay with me here.
Isaac is very young. One might assume pre-school age. Possibly even younger considering some of the many references to Number One and poop through the game. Too young to toilet train or fascinated by bodily fluids (including his tears of course) - possibly both - or just a case of a kid that is having trouble with the concept using the toilet yet (though you will see that I think the first as I continue). But he is also very smart. Possibly a young genius type that is too smart for his life experience. He is also possibly completely aware of his entire life from the point he was in his mother's womb with a brain developed enough to learn, to his current age... and his brain is only learning faster. A true wunderkind.

Being both young and smart, his short life up to now has been VERY traumatic to him. Being born (and remembering it all clearly) and having to cope with not being able to talk or walk or do anything, but cry for attention (as his muscles refused to work even though his brain told them to and his body can't control itself because it was not developed enough).

All of this has led young Isaac to be a bit of a delinquent youth at a very young age and his mother is of a religious bent (though her zealous nature in her religion is all made up by Isaac, or at least exaggerated greatly) and she punishes Isaac by not sparing the rod (using a wooden spoon for a spanking, or maybe a belt on occasions when he has been extraordinarily bad). She may or may not be expressly abusive, but that is not important for the theory, and more than likely, she is not as abusive as one might see based on Isaac's imagination, she is simply punishing a bad kid and trying her best to hopefully turn him into a kid that is good.

Being so smart did have some social struggles that were unfortunately brought to bear for poor Isaac.

One, his father did leave. He could not cope with a child that was smarter than him at such a young age (or at least showing signs of being smarter) and/or he simply did not understand his son. Perhaps he was simply an ass-hole dad too, it doesn't matter, the point is, he left. Two, Isaac's vastly superior intellect compared to anyone else made it hard for him to identify with children at a day care or pre-school of his own age, and anyone that he might have been able to have some form of conversation with would have been too old to try to talk with the small child. Plus the fact that even if someone had wanted to try and converse with him, his young age made his life experience too limiting to have any real conversations about anything "real".

Isaac was kept at home as a result of the awkward nature of his interactions and his generally anti-social standing with other children.

This along with a chest full of toys - including a copy of a role playing game of some sort, and the requisite dice - has led Isaac to create for himself a game to try and bring the ideas buzzing in his head and his own emotional struggles into a more cohesive whole. Unfortunately for him, he is not that good at writing yet and can only draw in a crude manner. Obviously he only has access to crayons as well. He has created alternate egos and imaginary friends along the way and incorporated these into his little game.

Many of the items one finds in the game are simply household items or elements of Isaac's fantasies and imaginings being brought into the fold. His brain is still that of a child despite being so smart and so the rules are also always in flux and difficult to pin down for him. He makes up some as he goes (play-testing over and over as anyone might) and some he writes down when he can figure out "the math" of it. Since he has not been to school yet, his math is often wrong (leading to many inconsistencies in the game and some just plain missing or incorrect).

The game has even been played out in his basement in a live action format, hence the addition of things such as spiders and flies. But of course a simple spider (or fly) is not a very good enemy as one levels up, so he creates many variations on them in more powerful forms, including boss monsters with themselves having even more variations.

The many elements in the game that seem abusive, or religious, or sadistic, or masochistic are simply exaggerations of Isaac's upbringing with his mother combined with his own 'too smart for his own age' brain and imagination. Truly there is nothing sadistic in his imagination, he is simply trying to make a fun game to pass the time in his loneliness. The true tragedy is that he is simply a lonely boy who does not play well with others due to his youth and smarts. Something that will change as he gets older, of course, but at this point in his life it all seems hopeless (hence some of the themes in the game).

The set up of the game is such because of the games Isaac has played in his youth so far on his Nintendo Gameboy. One day maybe he will make his own game, but of course he does not fully understand how to code yet so right now the game is pen and paper (and so far only a few pages worth in crayon... mostly pictures since even his intelligent brain gets distracted like a child and he ends up drawing a cool picture instead of writing down some odd rule he is already struggling to get from his brain to the page.)

As to some of the themes of animal cruelty or eating animal food (or rotten food) in the game, well, he IS a small child, probably had a pet or two, and after they died (or an accident happened) Isaac might have done some exploratory post-mortem experiments on the dead pets. He is not disturbed (we hope), just curious. When it comes to gaining health from the food, he has probably had some of that food before... again, still a small child.

Finally, a note on all the dead baby references and Bob (Bob's Rotten head etc). We do not know exactly what Isaac found when he went into the basement. And the primary theme is of his toy chest (a place of safety turned into a horrible nightmare) all starting in the basement...

When Isaac went into the basement for the first time to play his game in live action, he found (among other simple and normal things) something very bad. He of course did not know it was bad, but it traumatized his small brain and caused him to retreat to the safety of his mother (as evidenced by The Womb) and fight his fears with a LOVING mother who told him it would all be okay.

In the end, he ended up back with his toys, in his room, with that secret entrance to the basement still there... Bob's Curse forever in the back of his mind. And so his game is both a fun enjoyment for a boy that will one day become a game designer (or a serial killer, we hope the former) and has all the elements of his life up until now. Write what you know as they say.

Some after thoughts about the "main bosses" of his game.

Mom is represented because when Isaac found "Bob" in the basement, his mother was both terrified for her son and furious he had done something so foolish as going down into a place he did not understand. (She of course had that all cleaned up and taken care of and possibly even locked the door Isaac found in his room... which Isaac of course has a key to, hence the keys and locked doors figuring so prominently throughout the game.) Her fury scared him until after he understood it was not directed at him, but that doesn't stop him from liking the idea of the giant foot of Mom smashing down on his player character! She did, after al,l kick down the basement door to get at whoever was causing her son to scream bloody murder (with knife in hand)!

Satan (added in the Halloween update) is... Satan. Isaac's own Halloweens are not filled with the fun costumes and candy of other kids because his mother doesn't believe in that sort of thing - hence there is no candy in the game... what kid would NOT add candy in a game of their making if they had candy a lot? So after his mother's explanation of why they do not celebrate Halloween, Isaac incorporated the horrible beast of Satan into his game.

Mom's Heart and It Lives are a little bit weirder and difficult for me to explain (or understand) but may be due to his experiences at birth and the fact he remembers it all. Something most of us "normal" people forget of our past. And for good reason.

Isaac himself, and why in the Cathedral? Well, what better boss to have as the epic end boss than yourself? And what better place to have as the final dungeon than not a dungeon at all? After all, if you were going to make yourself into a boss, would YOU live in some horrible place, or a big beautiful cathedral?

Finally, Blue Baby/??? and the Chest. Isaac has been traumatized by his experiences in the basement with Bob and sometimes his fears lead him to hide in his toy chest. It is a safe and secure place for him to hide in. This has led him sometimes to a lack of air. Not completely, of course, as his chest is not air tight, but he has had trouble breathing on more than one occasion in there. With nothing to keep him occupied in the chest but his own fears and memories and imagination, he has created the ultimate "boss" in the ultimate dungeon. His own toy chest (evidenced more so that it IS a "toy" chest by the fact that you gain four items on entering (with enough keys that is)) and his own dead form. Death has of course been explained to him at least once if not many times (Bob, Tammy, Max, and Guppy to name a few) and so he knows that "death is the end" and that no one comes back. But hey, he is smart and creative and so before even getting to read or watch stories about zombies he has created one in his own game! And better yet... you get to PLAY as a zombie! WOO!

We will see what kinds of themes and dungeons and bosses enter the next stage of Isaac's little game in Rebirth. And if this little theory of mine holds true with those themes.

The story, especially with Wrath of the Lamb, is a metaphor for Isaac's coming of age.
Isaac is beginning to enter his teenage years, probably coping with depression, and the entire game is allegorical. To wit:
  • Isaac's mother is not abusive, nor attempting to kill him. This is a metaphor for increased tension between the two; as a single mother, she gets the brunt of his depression, outbursts, etc.
  • When fighting Mom's Heart, he is in fact hurting her with words, possibly via an argument. Similarly, It Lives may be a metaphor for either suicidal thoughts, or claiming he wishes he'd never been born.
  • Puberty pills can be found after Wrath of the Lamb, suggesting that Isaac is changing more and more.
  • All of Isaac's different personas aren't "playing pretend" in the traditional sense — rather, he's grappling with his identity, and trying on several different personas (Eve is a stint with goth/emo, Cain and Samson with being "badass" and/or a delinquent, Judas with being cool and classy, and Maggy with being cheerful and "normal"). He's likely also grappling with gender issues, which his traditionalist mother either doesn't understand, can't accept, or doesn't even know about.
  • There are three different final bosses with Wrath of the Lamb, all potential outcomes to a crisis of faith as he questions his beliefs. Defeating Satan represents Isaac staying a devout Christian, and possibly making peace with his mother. Defeating Isaac represents Isaac coming to terms with sin, and embracing agnosticism/atheism/a non-Christian faith.

Isaac suffers from Dissociative Identity Disorder.
First of all, if the majority of the game is taken at face value, Isaac has clearly had an abusive childhood — the sort of experience believed to foster DID. The other characters are, in fact, alternate personalities, who fight his mother in his place as a coping mechanism. In the Twelfth Ending, whichever personality takes down Isaac is, in fact, subsuming the real Isaac. Assuming Isaac beats The Cathedral, then a Split Personality Merge results instead.

Isaac's Dad abandoned the family a long time ago
In Wrath of the Lamb, you can pick up an item called Dad's Key. This item unlocks all the doors in any room, and is primarily designed to allow you to run away from conflict.
  • Confirmed with ending 13.

Conquest is, in fact, War having taken a level in badass.
Of the original Four Harbringers of the game, War is almost always considered the easiest to fight — this in spite of being, you know, the personification of ALL COMBAT. Conquest only appears on the later levels, either replacing War or even after defeating him, and the distinction between Conquest's and War's domains is very minimal (hence why Conquest is replaced with Pestilence in most modern depictions of the Horsemen in the first place). Finally, their abilities are very similar:
  • War is the only one of the "Harbringers proper" to charge multiple times in a row, and will often charge after a standard attack. Conquest has the unique ability to create multiple bodies to charge at once.
  • War can raise his horse to the sky to summon troll bombs. Conquest can also raise his horse to the sky, summoning pillars of holy light.
  • On a more meta level, when Conquest appears, you may receive the boss intro screen for War instead. Glitch, or HINT?

Completing and using The Polaroid brings the Stable Time Loop, and Isaac's suffering, to an end.
Completing The Cathedral with six characters unlocks an item called the Polaroid. Take it into the fight with Isaac, and rather than fighting him, you instead fight ??? / Bluebaby. By the end of the fight, he will rise in a column of light and Ascend to a Higher Plane of Existence, just like Isaac did in his previous fights with him. After this, Ending 12 makes a lot more sense. His previous suicide attempt failed and turned him into Bluebaby. However, he managed to free himself and send himself to heaven by defeating him. This sinks in right after he does so... and he then realizes that he must kill himself and turn himself into Bluebaby once more to get his redemption and peace.

He refuses to leave without a ten-inch saxophone, a twelve pound bowling ball, a glow in the dark snorkel, and a chainsaw, because they give him super powers. Like the ability to survive a plane crash.
  • He didn't survive the plane crash because of superpowers, it was because he had his tray table up, and his seat back in the full up-right position!

Isaac is Isaac Clarke
Being very young during the events of this game, he is quick to block it all out of his mind after it's over. However, the experience he gains from fighting all of these horrors stays with him into adulthood, enabling him to instantly Take a Level In Badass when he has to fight Necromorphs.
  • We do found out in the expanded media that Isaac Clark's mom was sucked into Unitology and his father left when he was really young. So if we assume that his mom squandered their money on Unitology, went crazy over time as she was hearing voices in her head (the voice of Altman to her), and tried to kill her son for the purpose of Convergence, this theory checks out.

In the true ending, Isaac has become convinced that his mother is right.
The book he's reading as he hides from his mother in the chest is the Bible, and he's been tearing out pages to write down his adventures on the back — and reading Bible stories, which terrify him even more. When Isaac goes down to Sheol, he's sinking deeper into his fantasies and deeper into terror of his monstrous mother; the fight with Satan represents, at once, the end of his fantasy and full integration into it (read: the multiple personalities fusing and hiding in the chest to "escape his mother", suffocating him). When fighting Isaac, Isaac decides that his mother is right: he is corrupted and unworthy of life. This is represented by his looking like a demon in the mirror. When he eyes the chest, he has decided to hide in it and suffocate himself to death.

Neither God nor Satan demanded Isaac's mother to murder her son.
The voice at the beginning telling his mom that her son was corrupt belonged to her husband. After unlocking Ending 13, it shows a series of photos from Isaac's life: Isaac and his happy parents, Isaac dressed as Magdalene and his still happy mother, Isaac's parents without him, Isaac sad and alone, Isaac's shadow in the shape of a demon, Isaac crying naked by the chest, Isaac's mother attempting to kill him, and Isaac and his mother watching his father leave.

Isaac's mother was fine and even supportive as her son took on separate identities. She loved him regardless of what he decided to be. His father, on the other hand, didn't. He was the one telling his mom that Isaac had become corrupted and needed to be saved (with this in mind, it suddenly makes sense as to why she also takes Isaac's clothing during her cleansing montage). Eventually his demands became more severe until the choice came down to Isaac or his father — "to prove you love me above all else." His mother then did try to kill her son, but was stopped at the last moment not by the literal bible, but her faith. Isaac's father, either disgusted at what his wife tried to do or by her accepting Isaac's "sinful" ways, leaves.

This idea makes another theory more prominent: the entire game and fight against Satan and himself is all in Isaac's head. After being mentally scarred by his mother trying to kill him, his father abandoning them, and everything they'd said to imply it was his own fault entirely, Isaac locked himself in his chest with all his toys and clothes. The game is his dying mind scrambling up his memories, hating himself, and attempting to justify the actions of everyone around him. Only by bringing the polaroid to ??? (his dead self) in the Chest does he begin to correctly remember what actually happened, but by then it's too late and his real memories can only flash before his eyes.
  • Based on a recent interview with Edmund, this seems quite likely. Specifically, his mother's side of the family were fairly permissive Catholics while his father's side of the family were fundamentalists of the "Dungeons and Dragons are Satanist indoctrination!" sort, and he mentioned that these experiences heavily influenced the creation of the game.

Isaac's father leaving in the True Ending is a metaphor.
If we assume that most of the game is metaphorical, and that most of the photographs are as well — e.g. that Isaac wasn't really fighting against Satan/his own inner sin, that his Mother never really tried to kill him, etc. — then why not the final one? In actuality, Isaac's father died, and his mother (though not nearly as abusive as she's portrayed) grew cold and distant due to his loss, one of the few acts of kindness she was still able to show being to reassure her son that Daddy was in heaven now. And if all kids go to heaven, there's a toy chest right there that might be airtight...

Isaac did not succeed in suffocating himself in the toy chest.
When you kill Isaac, it represents Isaac deciding that he is indeed corrupted by sin and should bring himself out of the world. However, there are two primary reasons for this theory: One, it's a goddamn toybox! The things would surely be childproofed. And two, the True Final Boss is the Blue Baby, representing Isaac's death by suffocation. In the final ending, you kill him, and in doing so, Isaac decides that though life is hard, those happy memories are worth it, and he'll persevere.
  • Note that in order to fight Blue Baby, you have to obtain The Polaroid, a memento of those happier times. Without it, Isaac gives in to despair — but with it, he realizes that there's still hope.

Or gets bored of waiting to suffocate in a toy box that isn't airtight, whichever.

The game itself is specifically designed to be a metaphor for a religious text.
To wit: It's a game that relates a tale of a child whose parent(s?) has/have it in for him, and is forced to murder them for his own well-being, and that takes several elements from Abrahamic mythology (duh). However, what really cements it is this page.

The game is intended to spawn wild theories. Its ambiguousness and heavy use of metaphor point to this, because this allows people to interpret it in any number of ways, just like a religious text. You can interpret the whole game as a metaphor, or bits as metaphorical, or damn near nothing as metaphorical! You can decide that Mom is in fact abusive, or that it's an exaggeration or a construct! Edmund and Florian made the game with the exact intent of spawning a Talmud of sorts.

Another theory on the meaning of the game
The entire game is a metaphor about how Isaac preserves the basement after he is chased in it. The photos show a happy family, and things aren't necessarily in order. Everything about the game is Isaac's view. The enemies in the basement? How Isaac interprets what he sees down there; either stillbirths or horrific dolls. Mulligans are ones infested with flies, other humanoid enemies represent other things, such as ones without eyes, or ones with only a functional head. The flies, mostly friendly to Isaac, come in two variants. A housefly, which Isaac is used to, and enemy flies. Red flies are mosquitoes, and bite him when they land, black flies are houseflies, harmless so Isaac sees them as friends. Pooters and such are wasps, but rather than stinging him, they shoot. His powerups are his toys, and between coping with the horror of his basement and so many odd things, and seeing his toys again, his scared mind decides to play games. After the first incident, Isaac got curious and kept going down there, seeing as his mother kickstarted it, he saw her as his "boss" when, in reality, she calmed down after her first rage, and saw what she had done; letting Isaac play downstairs, letting him look, but if he got too scared he would run back upstairs, I.E. game over. After 10 times, he becomes so confident in his abilities he starts to play a new game with them.

Each aspect of Isaac is different. Original Isaac was the one who was running; Eve is the manifestation of his depression, that he is weak and needs pain to keep going, remind him of who he is. Maggy was his imitation of his mother, and had the most positive outlook at life, with the most health as he believed God was with him, just like mom. Judas was his belief that he couldn't be trusted, once again low health, but felt that he had power in his own decisions, the high attack. Cain was the belief that he killed his brothers by being alive, so he "stole" their life from them, and he was lucky to be alive, the highest luck. Samson, his final one, he felt empowered, he knew how to work around his "enemies", the more there were the more powerful he needed to be for each challenge ahead of him. ??? was his cautious run, just checking around for stuff, why he is so willing to go upstairs.

The mirror ending shows his fear about being what his mother had believed, hence his restored faith in his mother after she got hit with the bible. After fighting the Devil, he realizes that he had become so engrossed in his game that he's become violent, seeing as evil is supposed to have violent urges, swatting flies in the basement. The heaven ending, which canonically comes first according to Word of God, is him seeing what happened, that he had given himself to heaven, but did so violently, and solved his problem as such. The chest, when he is locked in it, he finally sees, in a moment of reflection, that it is he who has to decide how sinful he is, as he knows who he hurts, finally seeing the pictures again, the sin his mother and father had done so innocently, letting him come out of the toy box stronger in person.

The Blue Baby is... Isaac from the fifth ending!
What? Ok yeah, I'm three final bosses too late for this to be a real theory, but come on. Who are you to say which endings are canon?

The first run of the game always ends with the reveal that it was a story he was illustrating, but then Mom bursts in and tries to kill him for real. Because he subconsciously associated his mother's overzealous Christianity with her increasing neglect, he incorporates Christian symbolism in with various monsters he dreamed up for the story. As things go on, elements of past drawings incorporate themselves into his story, particularly his earlier works. At some point, he realizes what happened and decides to draw his mother aborting him in an attempt to prevent this all from happening. After killing himself as a fetus, he goes on to either heaven or hell. If he reaches heaven, he must destroy himself as a consequence for the paradox he created before. Afterwards, he either ceases to exist, or, if he has the Polaroid, convinces himself it was All Just a Dream, negating everything that happened.

We're going to see a big rise in numbers of kids called "Isaac".
Previously famous Isaacs were all stuffy old scientists like Newton and Asimov. Now a generation of gamers will look at a newborn child, bawling with its oversized, toothless head and think "Hey, it's Isaac!"

Sister Magdalene.
Just a small one, but something I think a lot of people might have looked over. In the game, you can get an item called "Sister Maggy" which is essentially a fetus, possibly an aborted or stillbirthed one. Now, one of the first characters you unlock is a "Magdalene", which is basically Isaac in a wig. Now note that most people call Magdalene "Maggy" as it's shorter. It's very possible that Magdalene was a sister Isaac was going to have, but who was stillborn. In an attempt to please his mom, or perhaps thinking himself responsible in some way, he dresses up as Magdalene by putting on a wig. The reason Magdalene has more heart containers at the start as well as a healing item, is that he feels good about himself trying to "atone" for it, as well as the healing item might be more metaphorical for healing the damage done to his mother and the family. If we want to stretch this further, this might be why his father left the family, as we can see the 13th ending. This might be further evidenced by the 13th ending, in which we can see Isaac dressing up as Maggy even before his mother went insane

Isaac's mom remarried.
Another theory taking the game from a symbolic perspective. After Isaac's father died or left, whichever it was, his mother managed to find love again. However, Isaac felt like his mom didn't care about him any more, because she spent all her time with this new and strange man she loved "above all else". His new stepfather was stern and restrictive, and especially disapproving of Isaac's tendency to dress like a girl. So, he expressed his feelings through his drawings, writing a story about his mom's worship of this new man and how, he believed, she would kill him if "her god" asked her to.

Guppy is the key to EVERYTHING.
Isaac's will leaves things to Guppy, a cat who is clearly dead since you can find various parts of him during a run. If you find 3 parts of him, Isaac transforms into an anthropomorphic version of Guppy with powers. Now consider that a lot of Guppy items show up in the Satan rooms.

Isaac had a cat named Guppy who was legitimately evil. Eventually Guppy died, but young Isaac never sort of accepted it (being a baby and having no concept of permanent death yet). He was delusional that his cat was still alive and keeping its evil essence around by treating it as if it were. God noticed Isaac's affection for the demonic cat and how dangerous it could be and told his mother of the corruption, leading to the plot of the game. Satan, meanwhile, tempts Isaac with giving up his soul (his life hearts and soul hearts) to be with Guppy again by offering him parts. Attaining enough parts causes a profane transformation where Guppy and Isaac become one, granting demonic cat Guppy access to our world.

Isaac is Infected.
The trap door to the basement in his room is a gateway to the Linear Maze, which ends somewhere in Chessboards Five or Six. The trip gave him an initial Twist of ballistic tears, and whatever power-ups he gathers are further Twists, reflected in his increasingly mutated appearance and expanded abilities. The monsters he's having to deal with are either Actors playing out their roles in a Caretaker's drama, or (in the case of the Mulligans and Hivers) other people who're lost in Wonderland and too insane to find a way back to Chessboard Zero.

Isaac's Mom, in this theory, is being manipulated either by the Army of No, or one of the Caretakers' lackeys impersonating God. The boss fight against her is actually against her Shadow after its tormentors have had their way with it.
  • Satan is a Caretaker, and Boss Isaac and Boss Blue Baby are Isaac's own Dissociated Shadows.

The whole game is Isaac coping with his sister's death.
The theory is best summed up with this handy graph. The only canonical endings are 12 (Isaac contemplates suicide), and either 11 (Isaac goes through with it) or 13 (Isaac decides against it). Note that beating Satan (commiting suicide) is easier then beating ??? (overcoming grief).

The game is in Isaac's head but still goes to reality for some of the endings.
Most of the game is in Isaac's head as he travels through the basement fighting monsters that he imagines. He writes down his adventures as the different personalities he has, representing the characters. Most endings represent him taking toys out of his toy chest until the tenth ending, where he realizes that if he continues for too long he'll cause himself to die because of the lack of bodily needs, thus he is incredibly scared. In the 12th ending he reads the bible and, with the realization and shame that he is so sinful, imagines himself as a demon. In the 11th ending he goes through all his personalities (and a demon to represent his sins) and ends up locking himself in the chest to get away from his mother. The reason he tried to do so is because he no longer knew the difference from reality and "the game". Something to note is that ending 12 comes before ending 11. However, in the 13th ending Isaac finally remembers all the good times he had, also the sadness of his father's death, from the photos in the chest and as such, decided that suicide isn't worth it.

Isaac's last name is Jogues, and the other characters and him are all martyrs.
Isaac Joques, the real life one, has been a martyr along with other martyrs for dying for their faith for preaching Christ's love. Now what was the unlockable credtis theme for beating the game 10 times and getting baby blue?

Isaac survives, what ever this is, represses it and grows up into Isaac
It's why Issac Clark is so good at dealing with markers, He's been though this sort of thing before, but either does not fully remember it, thinks it was a dream, or it was a dream or something, but nether the less he has experience with surviving a body horror infused world.
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