After the player acquires the G.E.C.K., the Wanderer is ambushed by the Enclave and captured.ДЄt the Enclave base at Raven Rock, the player is freed from their cell by the Enclave leader, President John Henry Eden, who requests a private audience with them. The player finds the Vault to be a testing site for the FEV (Forced Evolutionary Virus), and the source of the Super Mutants in the Capital Wasteland. With Project Purity still inoperational even with the Enclave occupying the site, the player travels to Vault 87 to find a G.E.C.K. Li flee to the ruins of the Pentagon, now a base for the Brotherhood of Steel and now known as the Citadel. James floods the project's control room with radiation to stop the Enclave military leader, Colonel Augustus Autumn, from taking control of it, killing himself (but Autumn survives), his last words urging his child to run. James and Doctor Li lead a team of Rivet City scientists to the memorial with intent to restart the project, but the memorial is invaded by the Enclave, a powerful military organization formed from the remnants of the pre-War United States government. James and the player return to Rivet City, and James reveals he sought out Braun for information on the Garden of Eden Creation Kit (G.E.C.K.), a device that contains the components needed to finally activate Project Purity. However, continued delays and Catherine's death during childbirth put an end to the project, and James took the player's character as a newborn to raise them in the safety of Vault 101.ДЄfter investigating the Jefferson Memorial, the Lone Wanderer tracks James to Vault 112, and frees him from a virtual reality program being run by the Vault's sadistic Overseer, Dr. Doctor Li informs the player of Project Purity, a plan conceived by Catherine and James to purify all the water in the Tidal Basin and eventually the entire Potomac River with a giant water purifier built in the Jefferson Memorial. Here the player meets Doctor Li, a scientist who worked alongside the player's father. The player travels to Rivet City, a derelict aircraft carrier now serving as a fortified human settlement.

The search for James takes the character on a journey through the Wasteland, first to the nearby town of Megaton, named for the undetonated atomic bomb at the center of town, then the Galaxy News Radio station, whose enthusiastic DJ Three Dog gives the player the moniker of 'The Lone Wanderer'. The main quest begins after the player is forced to flee Vault 101 when James leaves the vault, throwing it into anarchy and causing the paranoid Overseer to send his security force after the player. James frequently makes comments about the player character's deceased mother Catherine, and her favorite Bible passage, Revelation 21:6, which speaks of 'the waters of life'. The introductory sequence introduces the Lone Wanderer (player) to their character's father James, a doctor and scientist in Vault 101.

Fallout 3 pre war theme