Crackdown takes place in the fictional metropolis of Pacific City, whose several districts and areas are divided among four islands. The city is controlled by three crime organizations: Los Muertos, of Central American origin; an Eastern European gang, the Volk (which means “wolf” in Russian); and the formerly above-board Shai-Gen Corporation, from East Asia.

According to the Agency, a new medical student named Catalina Thorne was accepted into the Agency as a scientist. However she was found to have been performing her own unauthorized experiments and was kicked out. Afterwards, her life was ruined, with her blaming the Agency. Later, she broke into the Agency cloning facility which housed the original agents, and introduced a virus into them which mutated the already genetically modified Agents, who became mindless and enraged, going on a killing spree before dying hours later. She then went on to destroy the research labs, sending the project back to square one and singlehandedly destroying the Agent program.