The game revolves around rapper 50 Cent. The co-player's character can be one of three other members of the G-Unit crew: Tony Yayo, Lloyd Banks, or DJ Whoo Kid, each specializing in different combat techniques. The co-player is either run by the game or through online cooperative play.

The game is set in an urban warzone in an unnamed Middle Eastern country, where 50 Cent and G-Unit have been hired to play a rap concert. After the concert the promoter, Anwar is unable to pay them the US $10-million in cash he promised, but relents after being threatened. However, instead of the cash they were promised, he gives them a diamond-and-pearl encrusted human skull (bearing a striking resemblance to a platinum cast diamond encrusted skull by artist Damien Hirst) as collateral. This is promptly stolen by a paramilitary group led by the terrorist Kamal. 50 Cent (with the help of a selected G-Unit partner) decides to get it back at any cost and they soon find there is a much bigger enemy than Kamal. In the video game, he kills Kamal, Anwar, his enemies and he retrieves his skull.