The events of the game take place ten years after the NES installment. According to Capcom's press release, this iteration follows Nathan "RAD" Spencer (voiced by Mike Patton, Faith No More lead singer),, and a government operative working in the fictional Ascension City and an Operative for the Tactical Arms and Security Committee (or T.A.S.C) which specializes in training bionic commandos like Spencer. After he is betrayed by his own government and falsely imprisoned, the Great Bionic Purge begins. Before his execution, an experimental weapon detonates in Ascension City, unleashing an earthquake along with a radioactive shock wave that leaves the city destroyed and wiping out its populace, with the threat of an invasion from a terrorist force known as the "BioReign". Spencer is now freed to redeem his name along with the T.A.S.C's and is reunited with the bionic arm of which he was stripped.

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