Set in 1912, during the era of American exceptionalism, the protagonist of the game, former Pinkerton agent Booker DeWitt, is sent to the floating city of Columbia to find a young woman, Elizabeth, who has been held captive for the past 12 years.

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Although Booker rescues Elizabeth, the two are pursued by conflicting factions of the city, such as the nativists, who defend the Americans, and the Vox Populi, a rebel group representing ordinary people. Booker then realizes that Elizabeth is the central being for this conflict, and that she also has strange powers to manipulate rifts in the continuous space-time that plague Columbia.