The prologue explains how Isaac and his mother have a simple life; Isaac plays with his toys, and his mother watches Christian broadcasts on the television. Then, his mother hears a voice from above, thinking it is God, when it really is Satan. "God" says that Isaac is corrupted with sin. His mother removes Isaac's toys and clothes. Then, she locks Isaac in his room. "God" AKA Satan says once again that it isn't enough and he requires a sacrifice. The sacrifice will be Isaac. Isaac's mom goes to the kitchen, and grabs a butcher's knife. Isaac sees through a crack in his door. He finds a trapdoor under his rug and without hesitation he flings open the hatch. Just as his mother bursts through the door, he jumps down into the depths below.
In the game there are many monsters, ranging from flies and spiders to headless demon creatures that squeal and launch blood and poison bombs at you. You start out as Isaac, and shoot tears that do damage to monsters. You start out with one bomb. However, you can upgrade yourself by finding chests, blowing up blue tinted rocks with bombs, or finding treasure rooms that have power ups. My personal favorite power up is Epic Fetus, which allows you to launch missiles at the monsters and do massive amounts of damage. If you are unlucky like me, you can run into mini bosses, such as Wrath, Envy, and Gluttony. They are similar to bosses, except toned down and have less health. You can gain more health through power ups and Eternal Hearts.
When you finally reach the boss room, you must fight the boss unless you have the item "We must go deeper." After you kill a boss and everything else in the room, the room spawns a power up you can choose or not choose to pick up. It also gives you red hearts, soul hearts (a buffer for red hearts), or rarely, an Eternal Heart. Red hearts fill "container hearts" which are the max hearts you get (expanded by Eternal hearts or Power-ups).
Finally, you can proceed to the next level down. The levels are: Basement 1 (Cellar 1), Basement 2 (Cellar 2), Caves 1 (Catacombs 1), Caves 2 (Catacombs 2), Depths 1(Necropolis 1), Depths 2 (Necropolis 2), Womb 1 (Utero 1), Womb 2 (Utero 2), Sheol, Cathedral, and finally Chest. The Basements/Cellars, Caves/Catacombs, and Depths 1/Necropolis 1 have normal bosses, ranging from Widow, the upside-down spider, Pin, a worm, to the Four Horsemen of the Apocalypse.
When you reach Depths 2/Catacombs 2, the boss is Mom. You kill mom (weird huh!) and proceed to Mom's Heart in the Wombs/Uteros. After you beat Mom's Heart, you proceed to Sheol, and find Satan and kill him. Then, you proceed once more.
After beating Satan, you find yourself in a Cathedral. There you must find Isaac, and kill him. This is extremely strange and I don't know how to interpret this because essentially you are killing yourself. After beating yourself, a ginormous chest appears and you climb in. Note: This part is not supposed to be known until you actually find it. Therefore, readers must know that they are reading a spoiler for one of the most essential parts of the game. The FINAL Boss is ???. He is Isaac's dead brother, and you have to kill him again. He is the exact same as Isaac, except with more health, and more damage. After you beat him, another giant chest spawns, and when you look into it, you win. You have to win at least thirteen times to find all the endings, then to actually beat the game and become a platinum god, you have to find every single item.
You must be Mom, then restart. Then you beat Mom and Mom's Heart, and restart. Then you beat Mom, Mom's Heart, then Satan. This goes on and on.