Lilith Iyapo, a Black woman in her late twenties, Awakens in a sparse room, aware that it’s not her first time Awakening, but unsure where she is. The room is like a prison that she can’t leave and she only receives bland, tasteless food to eat. Sometimes, voices that she can’t see the source of answer her questions in ways that she doesn’t understand the meaning of, and Lilith begins to suspect that she is part of an experiment.
Lilith still remembers some parts of her past, including how her husband, Sam, and son, Ayre, died in a car crash. She also remembers how she is a survivor of a great war that killed most of the rest of humanity.
One day, one of Lilith’s captors, Jdahya, reveals himself. Lilith thinks at first that he is a tall, old man, but in fact, he turns out to be part of a species of aliens called the Oankali, who have hairlike tentacles on their bodies that they use to sense the world around them. They have taken Lilith to a massive ship that seems to be alive and has massive Earth-like environments inside it with structures that resemble trees.
Jdahya takes Lilith back to his family and introduces her to them. She learns that Oankali have three genders: male, female, and ooloi (which uses “it” pronouns). Lilith remains fearful around the Oankali, particularly Jdahya’s ooloi spouse, Kahguyaht, who is distant and condescending. Still, as more time passes, she begins to grow closer to some of them, in particular Jdahya’s ooloi child, Nikanj.
Lilith learns that she has been in a state of suspended animation for about 250 years, along with the other human survivors, who have all been preserved in formerly carnivorous plants. The Oankali describe themselves as “traders” of genes, with the ability to modify their own genes and combine them with other species. Their goal is eventually to create a hybrid race of offspring with humans that will remove humanity’s self-destructive flaws that led to war in the first place.
Lilith learns that she has been chosen to lead a group of about 40 humans on a mission to begin resettling the Earth. Nikanj trains her in Oankali ways and eventually modifies her genome to make her more like the Oankali, giving her a photographic memory and a stronger body, including faster recovery from injuries.
The Oankali leave Lilith alone as she chooses which human to Awaken for the resettlement mission. After looking at several possibilities, she starts off with a White woman named Tate who was wealthy on earth and who becomes Lilith’s advisor. Among the other people Lilith Awakens are a man named Joseph, who becomes Lilith’s partner. Another is Curt, a former cop who is protective but also stubborn and close-minded.
From the beginning, Lilith faces suspicion among the humans she Awakens, with many of them accusing her of being too close to the Oankali. Peter and Jean emerge as some of her harshest critics until, one day, one of the Oankali accidentally kills Peter and a distraught Jean is placed back in suspended animation. Despite Joseph’s apprehensions about the Oankali, Lilith convinces him to undergo a procedure to become stronger, similar to what she went through with Nikanj. She, Joseph, and Nikanj lie down together in a process that, in addition to strengthening Joseph, also has a sexual element to it.
Once Lilith has a stable group, the Oankali allow her and the others to go to a portion of their ship that resembles a forest environment on Earth. They are accompanied by ooloi Oankali who will eventually become the mates of humans to create a new species. By this point, many humans, even those loyal to Lilith, have grown increasingly distrustful of the Oankali. They begin to speculate that perhaps they actually are on Earth, and a group led by Curt goes off on its own. Eventually, even Lilith agrees to leave the ooloi camp and go off exploring the forest in a group that includes Tate and Joseph.
The next morning, when Lilith’s group runs into Curt’s group, their old conflict comes to a head again, and Curt knocks Lilith out. When Lilith recovers and finds herself in the ooloi camp, she learns that Curt murdered Joseph in a rage, after witnessing one of Joseph’s wounds healing quickly and believing that this meant he was an alien. Lilith learns that, in spite of how the humans rebelled, all of them except Curt will be sent to Earth anyway to resettle it, since there are so few humans remaining. Lilith herself, however, must stay behind to train a new group of humans.
Lilith is disappointed that she’s no longer allowed to return home to Earth. She is further disappointed and surprised when she learns that earlier, during Joseph’s strengthening procedure, Nikanj impregnated her without her knowledge with a part-human-part-ooloi child. Although outwardly Lilith tells Nikanj that she will stay to help train the next generation of human settlers, she silently begins to believe that the Oankali breeding plan will lead to the eradication of humanity, and so she resolves to do whatever she can to preserve humanity’s future.