Second Son is set seven years after the ending of Infamous 2, in which Cole MacGrath activated the Ray Field Inhibitor (RFI) to destroy a Conduit (superhumans named for their ability to "channel" powers) named John White, also known as the Beast. The explosion that resulted was originally thought to have killed all Conduits across the globe; however, those outside of the blast radius or with a natural resistance have survived. Fearing the Conduits' abilities after the destruction of Empire City, the US eastern seaboard and the worldwide economy, the Department of Unified Protection (DUP) is formed. Now, major cities across the United States are heavily monitored for Conduit activity, whom the DUP have labeled collectively as "bio-terrorists".