The central plot of Fallout 3 deals with the main character trying to find his father, James. Shortly after the player turns 19, his father leaves mysteriously. The player, after being threatened by the Overseer and forced to kill him, pursues his father, tracking him first to a radio station, then to Rivet City, a derelict aircraft carrier now serving as a settlement. Here the player meets Doctor Li, who tells the player of Project Purity, a plan to remove the radiation from the water of the Tidal Basin, as means of helping to restore the environment, as plant and animal life can not hope to return to normal with the constant presence of radiation.

After investigating the lab of Project Purity, built inside the Jefferson Memorial rotunda. the player tracks him to Vault 108, and frees him from a virtual reality suspended animation. After returning to Rivet City, the player's father and Doctor Li return to the Project Purity lab, where James tells the player that the catalyst for Project Purity is a GECK. However, while helping James rekindle the lab equipment, the Enclave arrives, and James kills himself and several Enclave soldiers with a massive dose of radiation. After fleeing the lab, Li and the player arrive at the Pentagon, now the Citadel of the Brotherhood of Steel. After recovering, Li pleads with the player to find a GECK to finish James work. After finding one on the manifest of Vault 87, the player sets out to retrieve it. the player discovers a Vault that had been dedicated to creating and perfecting the FEV virus. After retrieving the GECK, the player is ambushed again by the Enclave, who take the player captive.