- Major characters
- The Chosen One · Tandi · Joanne Lynette · Dick Richardson · Frank Horrigan · Ken Lee · AHS-9 · Harold
- Dogmeat · John Cassidy · K-9 · Marcus · Myron · Skynet · Sulik
- Major factions
- Enclave · New California Republic
- Minor factions
- Brotherhood of Steel · Hubologists · New Khans · Shi
Come 2077, with total nuclear war rapidly arriving at America's doorstep, the President of the United States and a number of other United States government officials leave their posts to take refuge in a number of secret locations around the world. Among them was Control station Enclave. Here, the President himself set up a secret base from which the U.S.A. could continue to exist and wage war on China, with the eventual goal of retaking the continental United States.
The game takes place in the year 2241 on the West Coast of what used to be the United States of America, mostly in California and Nevada. Faced with the worst drought on record, the village elders of Arroyo ask the direct descendant of the Vault Dweller, referred to as the Chosen One, to retrieve a Garden of Eden Creation Kit (GECK) for Arroyo.