Chris Redfield returns to the series as the main character in Resident Evil 5, a game which takes place five years after Resident Evil 4. He is sent to Kijuju, Africa, where local agent Sheva Alomar joins him in the mission to apprehend Ricardo Irwing, who is trying to sell bio-weapons in the black market. Soon they are attacked by hordes of locals infected by an improved version of the "las plagas" parasite seen in Resident Evil 4, which they call "majini". As the story progresses, Chris discovers that some old fellows are behind the whole incident.

As well as including the concept of the "las plagas" parasite, this fifth part of the series also brings back the novel gameplay from the previous game. With an over the shoulder view, Chris confronts hordes of infected enemies that can throw objects and even shoot at you. They can be repelled with various guns, grenades, or using the knife and melee attacks if they get too close. This time though, Chris has a partner, Sheva, who accompanies him through all the game and can be controlled by a second player, with both characters having to keep an eye on each other to survive. The second player can enter and leave at any time playing locally through split screen or online through another console.

The mercenaries mode, which consists of closed levels where the player must survive a given time while defeating enemies to set up chains and earn points, also returns from Resident Evil 4.