The second season begins four months after the events of Kirby Plaza. Peter Petrelli, Matt Parkman, Nathan Petrelli, and Sylar have all survived the events of the season one finale, and are trying to return to ordinary lives despite their extraordinary abilities, with the exception of Sylar, who is on a quest to regain the use of his abilities.

The main plot arc of "Generations" deals with the Company and its research on the Shanti virus. This research is explored through the Company's founders, whose identities are revealed, as well as through the effects of various strains of the virus on The Haitian, Niki Sanders, Sylar, and others. An amnesiac Peter Petrelli observes the potential devastation of the virus in a future New York City. The "heroes" ultimately come together in an attempt to stop the release of a deadly strain of the virus and avert a global pandemic.