The game begins on July 9, 1993, approximately three days after the United States military set up a blockade surrounding the infected areas of Muldraugh, Riverside, West Point, and Rosewood, dubbed the Knox Evacuation. There is no cure for the Knox Infection, and it is invariably fatal. After being infected, the player will begin to experience anxiety and nausea, which will progressively worsen until the player eventually succumbs to the infection. However, the player is immune to the latter form of infection.

The infection is known to spread through saliva, blood, and later on, through water droplets in the air.

However, it is theorized by several characters on KnoxTalk, a radio station in the game, that it could be a prion disease, an act of God, or bio-terrorism. The cause and origin of the Knox Infection are unknown. After about July 18, most of these channels go off air. The lore of Project Zomboid and the Knox Event is given through radio broadcasts and TV channels. Project Zomboid is set in 1993, with the game starting by default on July 9 however, the start date and time can be changed in the game settings. The latest stable release is Build 41, released in December 2021, which includes animation and combat overhauls, new audio and music, the city of Louisville, Kentucky, and revamped multiplayer by General Arcade. Project Zomboid is The Indie Stone's first commercially released game. Since then, Project Zomboid has appeared on Steam Early Access and continues development to this day. In 2011, The Indie Stone were subject to a high-profile setback within the indie gaming community following the theft of two laptops containing the game's code. It was one of the first five games released on the alpha funding section of the gaming portal Desura.

The game is set in the post-apocalyptic, zombie-infested exclusion zone of the fictional Knox County, Kentucky, United States, where the player is challenged to survive for as long as possible before inevitably dying. Project Zomboid is an open-world isometric video game in development by British and Canadian independent developer The Indie Stone.

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