After a strange disease —deemed the Sickness — seems to have wiped out all the adults and young children in the world, the surviving adolescents band together in tribes in order to survive. Jefferson and his best friend, Donna, are part of the Washington Square tribe in New York City. The teens in this group work together to find food in the surrounding buildings. Jefferson’s older brother, Washington, is the leader of the tribe. Strong and charismatic, Washington has kept the teens working together and relatively nonviolent. He is preparing Jefferson to take over leadership as he is approaching his 18th birthday. Whatever the Sickness is, it attacks the teens soon after they reach adulthood.
Jefferson faces down members of the Uptown tribe when they come to trade. The Uptowners bring a large pig, but what they want in exchange is girls. Jefferson refuses their offer. Before a fight can break out, Washington shoots the pig. Its dead weight is too much for the Uptowners to carry through the streets, especially since wild dogs will smell the blood. Washington dares the Uptowners to shoot him, as he will be turning 18 the following day. Instead, they tell him to enjoy the pain of the Sickness, but let Jefferson know they plan on taking revenge. Once the other tribe leaves, Jefferson and his friends bring the pig into their compound and celebrate. Fresh meat is a rarity, and the tribe plans on having a barbecue.
Washington succumbs to the Sickness days after his birthday. He turns the tribe over to Jefferson’s leadership. When Jefferson’s friend, Brainbox, an introverted genius, says he found information that may lead them to the cure of the disease, Jefferson decides to go on a quest to find it. First, they must get to the library across town to find an archived medical journal. Donna insists on going with them, and she brings along Peter, another of her friends, who is a homosexual and devout Christian.
As the four head out of their safety zone, they realize they are being followed by SeeThrough (who got her name because she is so tiny and thin). Jefferson tries to get her to go back to safety, but she insists she can help. When Jefferson tries to force her away, SeeThrough proves her abilities by incapacitating him with her martial arts moves. She is allowed to come with them. The five teens travel in a massive pickup truck that has been fitted with guns and bulletproof glass. They call it Chiquita. The modifications come in handy when a rival tribe shoots and throws Molotov cocktails at them.
The group survives the battle and takes stock of their injuries. One of Peter’s ears has been partially shot off, but other than that, they are OK. They stop at an abandoned drug store to see if they can scavenge more supplies. Jefferson finds some ADHD pills and pockets them as they can be used to trade with other tribes. The group finds the library without any additional incidents. Once inside, they split up to find the medical journal they need. SeeThrough stays outside to guard the truck.
The library, which has been rumored to be haunted, appears to be untouched. Jefferson and Donna search together, and he takes the moment to tell her that he loves her. Donna is flabbergasted, and although she is pretty sure she loves him, she is too afraid to admit it. Jefferson is upset, but before they can work through their feelings, they hear gunfire outside.
SeeThrough is trying to fend off a group of attacking Uptowners. The Uptowners destroy the truck, and the kids assume that SeeThrough is killed. Jefferson, Donna and Peter retreat inside the library and eventually are taken prisoner by its inhabitants.
This Uptown tribe worships and protects the information inside the library. They have cultivated the rumor that the building is haunted to keep the other tribes from destroying it. Once Jefferson admits that they were looking for information, the new tribe frees them. They take the kids to Brainbox, who has found the medical journal.
Their captors insist they celebrate together, and Jefferson is thrilled to smell roasting meat — until he realizes it is human flesh. SeeThrough, who is still alive, sneaks in and disarms one of the captors. They all manage to escape in the chaos that follows.
After spending the night in an abandoned hotel, Brainbox tells them that the possible cure for the Sickness can be found on Plum Island, a medical research laboratory. Jefferson advises the others to head back to the safety of Washington Square, but they refuse. They set off to the Bazaar, near Grand Central Station, a center for commerce in this new world. They are surprised to learn that bartering is not allowed; they must trade something to receive marked bills that they can then use to buy supplies and ammunition. Jefferson sells the pills he pocketed from the drugstore, and then he and SeeThrough participate in a fight ring in order to get the rest of the money they need. They discover that the Bazaar is run by the Uptowners who seek revenge against them. Once these Uptowners learn that Jefferson and his friends have entered their territory, the group is forced to escape, again, this time by fleeing through the unused subway tunnels. Along the way, they pick up Kath, a tough girl who wants out of the Uptown tribe. As they make their way through Central Park, a bear that escaped from the zoo kills SeeThrough.
Jefferson and his friends make it to Harlem, where they must now deal with the African-American tribe. Once again, they are taken prisoners. They discover this tribe is well-fed and has fresh produce. Their leader admits they have a farm nearby. They have also been able to use a 3-D printer to make guns out of plastic. Their plan is to take over the other territories, so they cannot let the Washington tribe go for fear they will warn the others. Jefferson arranges a deal: The Harlem tribe will use their resources and contacts to get them to Plum Island. In exchange, the Washington tribe will give them the cure to the Sickness.
Things go well for Jefferson and his friends as they take a boat to Plum Island. Once they arrive, they wait for daylight to land, but are attacked by a tribe of younger teens, who take them to the island as prisoners. Inside the research facility, they are introduced to The Old Man.
They had heard rumors that an adult survived, but no one knew if the rumors were true. The Old Man is a scientist with a rare genetic disorder, which allowed him to survive. Now he experiments on the teens that the others catch to try and find a cure. He injects Jefferson and Kath with the virus. Brainbox uses an antidote of his own creation to heal Jefferson, but Kath dies under The Old Man’s care.
Brainbox then covertly injects The Old Man with a toxic substance, and Jefferson chokes the man to death. Brainbox sets the others free. He has also managed to make contact with the world outside of New York City. Members of the United States Navy rescue the kids of the Washington Tribe who are on the island.