Grand Theft Auto V takes place five years after Grand Theft Auto IV and is now set in Los Santos. It centers around three protagonists: Michael, Trevor, and Franklin. New to the series is that the player can switch between the three characters on the fly. They each have different missions, lives, and personalities. They also often come together, especially for heists, a complex type of mission where a large operation needs to be planned and executed by determining a strategy and hiring additional henchmen. As with previous games in the series, the gameplay involves gunfights and takes place in a sprawling, open-world city where players get around by acquiring transport (cars, boats, helicopters, etc) through less than legal means. Players can roam the game world, complete story missions, and partake in various illegal activities, including shooting civilians, robbing people, destruction of cars, and the titular act of car theft. These lead to a wanted rating of up to five stars, sending in a police force in pursuit. Continuing to resist the police will also increase it. The wanted status is lost by getting out of sight or by spraying the car.

Michael, whilst hiding in the witness protection program as a result of a botched robbery nine years earlier, encounters Franklin who, in his capacity as a repo man, is sent to get a car from Michael's son Jimmy. Michael however realizes Franklin is being set up, so tells Franklin to crash his son's car into the dealership that sent him. After that, they become friends. One day, Michael discovers his wife in bed with another man, and with Franklin's help, chases him to a mansion, which they promptly burn to the ground. The mansion, unfortunately, belongs to Mexican drug lord Martin Madrazo, who demands they compensate him for what they did. They successfully rob a jewelry store, and one of Michael's old partners Trevor hears of this and asks to team up with the other two, who agree. From here their lives begin to spiral out of control.