This novel tells the story of an alien invasion through the eyes of a teenage girl, Cassie Sullivan, who seeks to rescue her brother, Sammy, from the enemy. The story is offered through a few narrative lenses including brief passages by two other characters, namely Ben Parish, Cassie's pre-invasion crush, and another young man, Evan Walker, whose relationship with Cassie becomes complicated as she learns more about his true identity. The novel opens with an ominous, aphoristic passage about invasions, and then quickly shifts to Cassie's story.
Cassiopeia "Cassie" Sullivan is a survivor of an apocalyptic invasion of Earth by aliens who have transformed the world into an isolated wasteland through a series of plague-like waves. A very thoughtful Cassie details nostalgic memories of her life before the invasion as she fights for her survival. Cassie is shown to have fallen into a rhythm of survival, having established a sort of home base. She acquires food, water, toiletries, and other essentials by rummaging through abandoned stores, avoiding drones who will kill her if she's spotted.
On one such trip, she meets a young man in soldier's attire who is badly wounded, armed, and potentially dangerous. In a split decision, she kills him, leaving her with an internal conflict: she must protect herself from the aliens, and the aliens that look like humans, so she either saved herself from being killed, or she murdered an innocent and wounded soldier.
After this scene, two stories are presented in the opening of the book. First is the present narrative in which Cassie begins to journey toward Cincinnati. The second is a story about Cassie's world after the appearance of the alien mother-ship. Cassie's quest is complicated when she is badly injured after being shot by a "Silencer" with a sniper rifle. The flashbacks begin to explain what it is she has to do in Cincinnati.
In the flashback episodes, Cassie's family suffers through the first waves of the invasion. The first wave was an electromagnetic pulse that rendered all technology on Earth useless, killing many people who were in airplanes and vehicles at the time of the blast. The second wave was a literal wave. The aliens dropped giant beams into the Earth's fault-lines, causing tsunamis that killed all those who lived near the coast, approximately 3 billion people.
The third wave was a plague of disease carried through birds. This disease was fatal and gory, and after Cassie's mom died of the disease, her father took her and Sammy to seek refuge with other survivors. Eventually, the military came to their refugee camp to take the children to a safe place and took Sammy in a bus. Before Sammy went, he gave Cassie his teddy bear, and Cassie and her father were left behind. Cassie was sent to find an acquaintance of hers near an ash heap in the woods, but while she's gone, she heard gunshots. The military murdered all the survivors, and Cassie was only able to narrowly escape by killing a soldier.
Now back in the woods, Cassie realizes the fourth wave is the snipers or Silencers who are hunting the survivors. She is shot in the leg and escapes from the Silencer. She almost dies in a snowbank but is rescued by Evan Walker, with whom she shares a romance. After watching her father die, she is determined to get Sammy back.
Little does she know that her high school crush, Ben Parish, is taking care of Sammy, who joined him at Camp Haven to be trained as a soldier to fight the Others. Soon enough though, they realize that the Others are actually in control of the base and they are making them kill humans instead of Others. Ben's squad takes to the woods and Ben goes back to save Sammy.
When he goes back, he runs into Cassie, who is also in the middle of saving Sammy. The two join forces and run away together. They are almost caught by the Others, but with the help of Evan and a stolen Humvee commandeered by the squad, they all manage to get away to fight another day. The story ends there, with a sequel following it to finish the story.