Following the events of Infamous, Cole and Zeke wait in Empire City and are preparing to face the Beast, a superpowered entity that Kessler, Cole's alternate self from a different timeline, had warned them about. They meet Lucy Kuo, who knows of Dr. Wolfe, a scientist that worked on the development of the Ray Sphere the device that gave Cole his powers but at the cost of the lives of thousands of others in Empire City.

They arrive in New Marais, finding the city under control of a wealthy industrialist who has organized a human-purist Militia force to wipe out Conduits. (Conduits being hums that could possibly gain the power that Cole has.)