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 In 2004, Michael Townley, Trevor Philips, and Brad Snider partake in a failed robbery in Ludendorff, North Yankton, resulting in the first being presumed dead. Nine years later, Michael lives with his family in the city of Los Santos under the alias Michael De Santa, having made a secret agreement with the Federal Investigation Bureau (FIB)[j] agent Dave Norton to stay hidden. Across town, gangster Franklin Clinton is working for a corrupt car salesman and meets Michael while attempting to fraudulently repossess his son's car. The two later become friends. When Michael finds his wife sleeping with her tennis coach, he and Franklin chase the coach to a mansion, which Michael destroys in anger. The owner of the mansion, drug lord Martin Madrazo, demands compensation. Michael returns to a life of crime to obtain the money, enlisting Franklin as an accomplice. With the help of Michael's old friend Lester Crest, a disabled hacker, they rob a jewellery store to pay off the debt. Meanwhile, Trevor, who lives in squalor on the outskirts of Los Santos, hears of the heist and realises it was Michael's work; Trevor had believed Michael was killed in the Ludendorff heist. Trevor finds Michael and reunites with him, forcing Michael to reluctantly accept him back into his life.

As time goes on, the lives of the protagonists spiral out of control. Michael's criminal behaviour prompts his family to leave him. When he later becomes a movie producer, he comes into conflict with Devin Weston, a billionaire venture capitalist and corporate raider, who attempts to shut down Michael's studio. Michael thwarts his efforts and inadvertently kills his assistant, causing Devin to vow revenge. Meanwhile, Franklin must rescue his friend Lamar Davis from his former friend and rival gangster Harold "Stretch" Joseph, who attempts to kill them to prove himself to his new gang. Concurrently, Trevor attempts to consolidate his control over various black markets in Blaine County, waging war against The Lost outlaw motorcycle club, Latin American street gangs, rival meth dealers, private security firm Merryweather, and triad kingpin Wei Cheng.

Having broken his agreement with Dave by committing heists again, Michael is coerced by Dave and his superior, Steve Haines, to perform a series of operations alongside Franklin and Trevor to undermine the International Affairs Agency (IAA).[k] Under Steve's direction and with Lester's help, they attack a convoy carrying funds for the IAA and steal an experimental chemical weapon from an IAA lab. As Steve comes under increasing scrutiny, he forces Michael and Franklin to erase evidence against him from the FIB servers. Michael takes the opportunity to wipe the data on his activities, destroying Steve's leverage over him.