Enemies have predictable routines but occasionally do something mildly buggy that comes off as cheap. Sometimes this can be surpassed with skill, but other times it’s just dumb luck, which can be irritating. There is a high level of difficulty in accordance with the roguelike genre. The enemies themselves are disturbing - blood and feces are used as weapons, fetus-like creatures are common (and implied to be Isaac’s miscarried siblings), and enemies emit distorted baby cries. Between levels, quick scenes are shown of Isaac’s dreams, which usually involve something horrible happening to him. Its treatment of Christianity was responsible for Nintendo’s initial aversion to the game (they have since relented, and it’s now available on 3DS and Wii U) and the reaction of certifying bodies like that of Germany, which referred to it as 'blasphemous'. It explores many taboo subjects from Christian scripture and mythology as well as childbirth and childhood, often in an ambiguous fashion (except for the brief cutscene in the prologue). 'The Binding of Isaac: Rebirth' is creepy, provocative, and unsettling. One room on each floor contains a boss, which awards Isaac with items upon defeat and also opens the door to the next level down.

Each floor of the dungeon has a set of rooms for Isaac to explore, filled with monsters, item chests, tarot cards, shops, and other curiosities. It hearkens back to ancient dungeon crawlers like 'The Legend of Zelda' and 'The Legend of Zelda: A Link to the Past'. The game controls like a twin-stick shooter, with Isaac’s movement determined by the left stick and his tear projectiles fired with the right (the face buttons can also be used to shoot the tears). Once in the basement, Isaac is temporarily safe from Mom, but soon discovers that the underground has a life of its own. Previously Mom had taken away all of Isaac’s toys and coloring books, and then locked him in a bare room, all because of God’s commands. The titular character is a naked, crying little boy who descends into the basement of his house after his mother has determined that the best way to serve her God is to slay her son, much like the actual binding of Isaac detailed in the biblical book of Genesis. 'The Binding of Isaac: Rebirth' is a top-down roguelike dungeon crawler.

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