Mayuko Shiraki is Tohru, Kyo, Yuki, Saki, and Arisa's homeroom teacher; what subject she teaches is never given, though in an author's note, Natsuki Takaya said she thinks Shiraki fits the image of a literature teacher. Shiraki is depicted as generally good-humored but sometimes aggressive—when Kyo attempts to leave class on Valentine's Day, she stops him at the door with a folder in his face and threatens to dye his hair black instead of orange, and once breaks up a fight between Hatsuharu and Kyo by dumping a bucket of water over them;she once demanded as a joke that, after some students familiarly addressed her "Mayu-chan-sensei," that they call her "Great Teacher Mayuko." Her parents, who worry about Shiraki being unmarried, run a bookstore where she sometimes helps out. Takaya said in an author's note that Shiraki is "possibly sad" that she is a woman and "secretly insecure of how tall she is," but since Hatori Sohma is tall too, they "might look pretty good together."

Shiraki is best friends with Kana, Hatori's former fiancee, and through she met Hatori, Shigure, and Ayame two years before the series begins. While Shiraki was attracted to Hatori, she was glad that Kana and Hatori were happy together. She dated Shigure for a month before breaking up, partly because Shigure was distant and partly because she was only dating him to alleviate her loneliness. She was at a loss when Kana and Hatori broke up, because Hatori had erased Kana's memory of the engagement. Shiraki still has feelings for Hatori, but resents Shigure's continuing interference in her life, even when it brings her closer to Hatori. In the final chapter, Shiraki and Hatori are shown as a couple, with Hatori inviting her on an Okinawa vacation.