The world has been taken over by virals, an altered race of vampiric creatures who kill and turn every human they can reach. Like traditional vampires, these creatures tend to hunt at night so humans are reasonably safe during the daytime. Humans can typically move around freely during the daytime though there are some daytime attacks that occur. The communities of humans who are surviving are usually forced to live behind huge walls with strict rules about guards and movement after dark.

The virals are manmade, the creation of research called Project Noah. Those infected with the virus are immortal and immune to human ailments. The original researchers hoped to create an immortality serum without the side effects. Amy Bellafonte, a young girl abandoned by her mother, is the only one to react as the researchers had hoped. The ultimate goal was to create a race of super-soldiers. When the virals break free, they cause the fall of civilizations and almost wipe out the human population.

Almost a century has passed when Amy finds her way to the Colony where a group of survivors are faced with the knowledge that the lights they burn all are about to fail. Those lights keep the virals at bay and without them the entire population of the Colony is doomed. Members of the Colony learn the answer to their problems may lie in Colorado, far from their California town. Though there is no mechanical transportation, circumstances prompt the group to set out with Amy. Along the way they discover the virals have killed off almost everyone and have begun, with a small group of humans, to create a system to raise humans to serve as a food source for the original virals. Their travels take them through dangerous situations until they find the original Project Noah site and learn about the research that caused the downfall of civilization.

Meanwhile, other communities are trying to survive and seeking ways to make decent lives for themselves and their families. They have constructed "hard boxes," small underground shelters capable of keeping virals at bay, for shelter in case someone is caught in the open when virals attack. In one such community, a group of families is caught in the open only to realize the virals themselves had hidden in the hard boxes.

In another region, a corrupt city has been created with the sole intention of providing food for the virals. In turn, the humans are drinking infected blood though not directly from the virals. This has made them immortal and very young in appearance, though they must continue to drink to maintain that. Each of the original twelve virals, known as "the Twelve," has infected others. When that member of the Twelve dies, all the virals die with him. As a group of travelers accompanied by Amy converge on that corrupt city, they come up with an idea to kill the remaining members of the twelve. The plan succeeds with Wolgast using a bomb to kill all the remaining Twelve except one, a viral named Anthony Carter who has already locked himself in an abandoned ship and is therefore unable to infect anyone else.