Three years after 'The Rising' began, Vanessa - a mysterious dead woman - is resurrected in a world now ruled by vampires. Holed up in an abandoned hospital with other human survivors, she fends off both vampires and treacherous humans and discovers special powers even she didn't know she had.

Vanessa is attacked and left for dead in the days leading up to "The Rising," causing Doc, Axel and the marines to retrieve her body and become marooned in a hospital.

The hospital's power source is damaged, jeopardizing the protective UV lights; Vanessa and Axel head into Seattle to scavenge parts, leaving the others to fight against the vampires and amongst themselves.

Vanessa and Mohamad head into the vampire-controlled streets in search of Vanessa's daughter; Cynthia is found dead at the hospital, and Doc thinks her apparent suicide is actually a deliberate murder; Vanessa is captured by vampires.

Vanessa, now in the clutches of Julius and his vampire brood, is forced to demonstrate her powers; the refugees discover a serial killer among the residents, and plot to wrestle control from Axel.

Vanessa and Susan are chased by mutated feral vampires in the sewers, arriving back at the hospital only after a hostile takeover.