The original Resident Evil revolves around a series of cannibalistic homicides that occur in the Arklay Mountains region, situated north of the fictional Raccoon City in 1998. The local police's Special Tactics and Rescue Squad (S.T.A.R.S.) are commissioned to investigate the sources of these murders. When Bravo Team, the initial team deployed to the area, fails to report back, Alpha Team goes on a rescue mission to find them. They are led to a seemingly abandoned mansion, where the team encounters Zombies and other creatures, leading them to discover the remains of most of their comrades in the house. In the end, it is revealed that the house is actually a front for a top-secret laboratory owned by the international Umbrella Corporation, and that the creatures are the result of experiments with a genetically modified virus called the T-Virus. Resident Evil 0 explores the cause of the viral outbreak and Bravo Team's ordeal prior to the events of the Mansion incident.

The following game, Resident Evil 2, takes place two months after the events of the original game in Raccoon City itself. With S.T.A.R.S. unable to convict Umbrella for their wrongdoings, the company continues their experiments within an underground facility. However, a botched attempt to steal a former scientist's (Dr. William Birkin) work results in the T-Virus being leaked into the city's sewage. This results in most of the city's population being turned into zombies, leaving only a few survivors trying to find a way to escape the city alive. The third game, Resident Evil 3: Nemesis, takes place around this same time period, and features a similar premise. The game concludes its story by depicting the city's ultimate destruction by a massive air strike. The Resident Evil: Outbreak series depicts the attempts of normal civilians trying to escape the city.

Resident Evil Code: Veronica depicts the previous games' survivors attempt to expose the Umbrella corporation and sabotage their operations. Code: Veronica reveals the existence of a rival corporation, who employs Albert Wesker, the crooked leader of the Raccoon City S.T.A.R.S. team, also developing their own bio-weapons.