The book switches point of view from Jane Takagi-Little and Akiko Ueno as the novel progresses. For Jane the plot is told through faxes and journal entries, for Akiko the plot is told through third person omniscient point of view. In America, Jane works with the Japanese film crew under the direction of "John" Ueno to film American housewives as they prepare their favorite dishes.
The show My American Wife! is sponsored by an American Beef company BEEF-EX that wishes to increase beef exports to Japan. "John" Ueno's job is to satisfy the network and BEEF-EX by finding and filming pretty white American women who make good looking beef dishes. "John", however, has an allergic reaction to the antibiotics in veal and the on-site production is handed over to Jane. Jane is intrigued by the existence of antibiotics in meat and she begins to dig deeper into beef production while trying to show more diverse families and dishes in her episodes of My American Wife!
As Jane pushes to show families of various ethnic backgrounds and physical abilities while showcasing dishes of pork, lamb, and vegetables she strains her relations with "John" Ueno her boss. In an attempt to pacify him, Jane takes him out drinking. When she takes him to his hotel room afterward he attempts to rape her but she escapes. All the while Jane's newfound relationship with musician Sloan begins intensifying as they secretly meet in various hotel rooms near Jane's production shoots. Eventually Jane becomes pregnant but persists in her quest for knowledge.
Meanwhile, in Japan, "John" Ueno orders his wife Akiko to watch every episode of My American Wife! adding that she must take a survey on her opinion of the show, and she must prepare the featured dish for him before he comes home. Throughout Akiko and "John's" interactions it becomes clear that he is routinely physically abusive to his wife. Akiko is malnourished and as such has stopped menstruating. This angers "John" as he desperately wants a child. "John" sends Akiko to a fertility specialist who claims Akiko's condition is her fault and calls her husband who reprimands her. Akiko, desperate for happiness, secretly faxes Jane Takagi-Little. When "John" finds out Akiko has not only faxed Jane but, Akiko does not want to be with him "John" beats and rapes her, landing Akiko in the hospital and pregnant.
At the same time, Jane is in Texas filming an episode for My American Wife! as a cover to discover the inner workings of a feedlot and slaughterhouse. The children of the family running this feedlot exhibit symptoms of hormone poisoning. When filming on the kill floor Jane has an accident and wakes up in the hospital to find she's had a miscarriage and has been fired from her job. After she gets out of the hospital her former co-workers admit to copying the footage of the slaughterhouse and the hormone poisoned children for her and Jane edits the tape herself into a documentary.
The documentary is widely distributed by the family of the hormone poisoned children and Jane and Sloan attempt to fix their relationship despite the miscarriage. Akiko leaves "John" staying with Jane for a short time before Jane uses the connections she made during the filming of My American Wife! to help Akiko get her own apartment.