A small pharmaceutical company called Maddicorp (located in Manhattan) is taken over by the late owner's son, Moses Maddigan, who allows the company to succumb to outside pressure and begin to develop biological weapons, allowing the company to grow financially and become a world-wide super power in the industry. An illegal experiment is conducted deep in the bowels of the Maddicorp complex, called "S.H.A.D.E." (Synthetic Heightening of Attributes and Dynamics Experiment), in which a team of geneticists worked hand in hand with another team of scientists to create a synthetic gene that could be manually spliced into a living human's DNA. The gene causes the subject to develop special abilities, unique to each person depending on their existing genetic structure. All of the subjects were either volunteers who were at rock bottom in their lives, or people taken from prisons, asylums, or off the streets that would not be missed.
The experiment is going well until one subject, Kane Kelly, who has unfortunately managed to remain conscious during his 2-year incubation in a liquid-filled stasis chamber, basically is driven insane. The liquid in the stasis chambers, which usually had been emptied, filtered, and refilled by machine periodically, needed to be sanitized manually due to a programming error. Kelly saw his chance during this and broke out of his chamber using his new-found abilities (he could manifest a nigh-invulnerable and super strong ethereal being that was bonded to his body), killing nearly every scientist involved in the project. He awoke every other subject and opened their chambers before leaving, allowing them to slowly regain consciousness and escape.
The game takes place a few years after this. Moses Maddigan now has a team of mercenaries dubbed "The Collection Agency," who search for and capture the subjects. Snow and Sabotage are the main protagonists.