The novel features a unique narrative structure, in which chapters alternate between the voices of Nick and Amy. In the first part, Nick's voice narrates events surrounding Amy's disappearance as they unfold. He counts the days from the date of her disappearance. Amy's chapters, on the other hand, take readers into the past, featuring entries from her diary from years earlier.
The novel opens on Nick and Amy's fifth wedding anniversary. The couple live in a rented home in the town of North Carthage, Missouri, having moved there two years prior from New York City. Amy was resentful of the move, but they had been struggling financially after both losing their jobs (Nick was a magazine writer). The deciding factor had been when Margo, Nick's twin sister (who had returned to Missouri after her own job loss) told him that their mother was dying. With their father also seriously ill, Nick agreed to move back to his hometown without even consulting Amy.
Nick now co-owns a bar with Margo, financed by a loan from Amy's trust fund, and works there part-time. Amy has not yet found work. Nick and Margo have a very close relationship, especially since she tends to adopt a "one of the boys" persona. Nick is anxious about an anniversary tradition he and Amy have in which she crafts elaborate treasure hunts for him to follow. In the past, these have been occasions for him to feel like he has failed, due to being unable to remember small details which Amy considers important. Nick also has a strained relationship with his father, who lives in a care home, suffering from Alzheimer's. He is an angry and misogynistic man and Nick has always been afraid of resembling him.
While at the bar on the day of the anniversary, Nick receives a phone call from his neighbor Carl, telling him that the front door to his house is open, and his cat (which is not allowed outside) is on the front step. Nick heads home to investigate, and finds an ominous scene. Details such as the iron and teakettle being on suggest that Amy did not purposefully leave the house and the living room shows signs of a struggle. Amy is nowhere to be found. After several unreturned calls and messages to Amy's cellphone, Nick calls the police. After investigating the scene, the cops call in two detectives, Detective Boney and Detective Gilpin. They ask a few questions about Amy, and Nick, hoping to avoid casting any suspicion on himself, lies several times. They then move to the police station to continue questioning him, and while there are no accusations made, Nick knows that as Amy's husband, he will be a prime suspect. When questioned about his whereabouts, he explains that he left the house at 7:30 am, went to the beach for a few hours, and then arrived at the bar around noon. He has no alibi for the time spent at the beach. He finally calls Amy's parents to tell them that she has disappeared and then spends the night at his sister's home.
Amy's journal begins in January 2005, detailing her first meeting with Nick. At the time, she makes a living writing personality quizzes, drawing on her education in psychology. She has grown up with parents who are both successful child psychologists and enjoy additional wealth and fame as authors of a popular children's book series about a character named Amazing Amy. She meets him at a party in New York, and is immediately struck by his good looks and Southern charm. After the party, the two share their first kiss. However, he doesn't call her afterwards and she doesn't see him again for eight months, until they run into each other on the street in September. She is immediately struck by the possibility of a long-term future with him, especially since she is tired of being single.
By 2007, Nick and Amy have married, and she describes in her journal the happy life they are leading together in New York, living in an expensive brownstone purchased for them by her parents. Her recollection of their anniversary treasure hunts are much more positive.
The novel immediately makes it clear that Nick and Amy have different perspectives on each other, and on their marriage. Nick is unhappy and embittered; he has been disappointed both professionally and personally. His discussion of his wife shows her to be angry, sharp-tongued, and harsh. Amy's diary, however, suggests a sweet, bubbly, and loving woman. Because the diary dates back to years earlier, at this point there is the possibility that Amy has simply has changed over time. This possibility creates suspense, leaving the reader curious as to how a marriage that had such a loving start could decline so sharply.
Deconstructing the idealization of marriage is a major theme of the novel, which becomes apparent from the beginning. Nick acknowledges at the very start of the novel that he does not understand what Amy is thinking or feeling. This admission is contrary to the idea of intimacy and sharing that is usually associated with marriage. Rather than supporting each other during economic troubles and tragedies (like the illness and death of Nick's mother), it seems that Amy has made Nick feel more like a failure. As Emma Teitel puts it, "The competing narration is evidence that marriage is a mystery unto itself, with or without a missing person's case" (64).
The importance of family, and the influence of family members, is also clearly established. Nick hates and resents his father, whose bitterness and misogyny have been exaggerated by Alzheimer's. Nick's father, however, has always been an angry and borderline abusive man. Growing up with a father like this has made Nick very anxious that people always like him, and desirous to prove that he is a "good guy."
There are also hints that despite his desire not to be like his father, Nick has a tendency to regard women in a negative light. He is very attached to his twin sister, Margo, but a major part of what he likes about her is that she does not behave in conventionally feminine ways. Margo is assertive, blunt, and has a crass sense of humor. This rapport puts Nick at ease, and makes him feel like he can be himself, in contrast to Amy's criticism and nagging.
Amy has also been influenced by her parents. Their interest in psychology was clearly passed down to her. Because Amy's parents were very successful, they were very demanding of their only child. The Elliotts both idealized Amy, and taught her from a young age that she was expected to be perfect at all times. Amy has largely been able to embody this perfection with her beauty, intelligence, and wit. However, Nick's comments on the state of their marriage would seem to suggest that she also demanded perfection from everyone around her, and that this alienated people.