The Lone Wanderer lived in Vault 101 without incident for nineteen years, but in 2277, 200 years after the Great War, James disappears without any explanation. The young Lone Wanderer, with the help of Amata Almodovar, leaves the safety of the Vault to look for James in the ruins of Washington, D.C. In order to find him, the Lone Wanderer travels across the wasteland following James's trail, searching for clues and speaking to the people he encountered to find out where he went. After finding him, Project Purity is put back on track, but the reunion is cut short when the Enclave commander, Augustus Autumn, arrives and demands ownership of the Project. James, unwilling to allow the project to fall into the hands of the Enclave, sacrifices himself by filling the control chamber of Project Purity with deadly amounts of radiation, in hopes of killing Colonel Autumn and the other soldiers. Colonel Autumn, however, survives. The Enclave take control of the project, but are unable to operate it.
After fleeing from the Jefferson Memorial building with the remainder of Project Purity staff, The Lone Wanderer takes refuge within the Citadel and enlists the help of the Brotherhood of Steel to retrieve a G.E.C.K. from Vault 87 for use in a soon-to-be-recaptured Project Purity. Because the G.E.C.K. is in a highly irradiated chamber, the Lone Wanderer must then choose whether to enlist the help of Fawkes, a friendly super mutant, or face the deadly amounts of radiation alone. Once the G.E.C.K. is retrieved, the Lone Wanderer is captured by Colonel Autumn and taken to Raven Rock. There, President Eden presents the Wanderer with a canister of modified FEV for insertion into Project Purity, which would poison any mutated creature drinking the purified water. It is unknown whether the Wanderer obeys this instruction, but it is known that Raven Rock is destroyed and Project Purity is recaptured with the aid of Liberty Prime. There, after finally stopping Colonel Autumn, the Wanderer and Sentinel Lyons are faced with the dilemma of who would enter the radiation-flooded chamber and activate the project. Once the purifier is activated the wasteland is finally given the greatest gift of all: fresh, clean drinking water.
The Lone Wanderer awakens two weeks later to face the consequences of their decisions so far and joins the Brotherhood as a knight, in their mission to distribute the newly-purified water and to hunt the Enclave remnants. This hunt would eventually put the Wanderer in control of an orbital strike. The Lone Wanderer either uses it to destroy the Citadel or the Enclave mobile base crawler. During or after the events of Fallout 3, the Lone Wanderer travels to various places such as The Pitt, Point Lookout, Mothership Zeta and participates in a simulation of the Anchorage Reclamation.