McMillen and Himsl released an expansion 'Wrath of the Lamb' in May 2012, but were limited from further expansion due to limitations with the Flash platform. The game soon gained popularity partially as a result of various Let's Play videos showcasing the title. McMillen had considered the title a risk but one he could take after the financial success of Super Meat Boy, and released it without much fanfare to Steam in September 2011, not expecting many sales.

The game was the result of a week-long game jam between McMillen and Himsl to develop a The Legend of Zelda-inspired roguelike that allowed McMillen to showcase his feelings about both positive and negative aspects of religion that he had come to discover from conflicts between his Catholic and born again Christian family members while growing up. Players control Isaac or one of seven other unlockable characters through a procedurally generated dungeon in a roguelike manner, fashioned after those of The Legend of Zelda, defeating monsters in real-time combat while collecting items and power-ups to defeat bosses and eventually Isaac's mother. In the game, Isaac's mother receives a message from God demanding the life of her son as proof of her faith, and Isaac, fearing for his life, flees into the monster-filled basement of their home where he must fight to survive. The game's title and plot are inspired by the Biblical story of the Binding of Isaac. It was released in 2011 for Microsoft Windows, then ported to OS X, and Linux. The Binding of Isaac is a roguelike video game designed by independent developers Edmund McMillen and Florian Himsl.

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