The plot is told in a series of substories, published monthly or as 2-3 per volume. While it begins with a monster of the week approach, with somewhat independent running chapters, the plot gradually becomes continuous and backstory is introduced. It focuses on the development of the characters and the relationships between them.
Sixteen-year-old Subaru Sumeragi, the main character, is a very powerful magician, the thirteenth head of the foremost family of onmyōji in Japan, which has served the Emperor for centuries. As such, he is called upon to solve various occult mysteries, or stumbles himself on people whom his kind nature compels him to help. These occurrences form the main plot of most chapters. He lives in Tokyo with his twin sister Hokuto, an exuberant girl whose chief occupations are to design eccentric clothing for herself and her brother, and to egg on their mutual friend Seishirō Sakurazuka, a kindly, 25-year-old veterinarian, when he declares his love for Subaru.
There are early hints that Seishirō may not be all that he appears. Hokuto jokes about him being a member of the family of Sakurazukamori, a clan of assassins who use onmyōjitsu to kill, and are pronounced to be the Sumeragis' opposite. Also, Subaru has dreams about having met someone under a cherry tree blooming out of season when he was but a small child, but he cannot quite recall what was being said. This person was actually Seishirō, upon whom Subaru stumbled when he had just performed a kill. According to the rules of the Sakurazukamori, Seishirō should have killed him, but impressed with the child's purity, he made a bet with him instead: He would meet Subaru again, and would then spend one year with him, protecting him and trying to love him. If, at the end of that year, he felt something for Subaru which distinguished him from a thing he could easily destroy, as he could not with any other person, then he would not kill him. To recognize him, he marked him with inverted pentagrams on both hands, the sign of the Sakurazukamori's prey. These marks are for most of the story hidden beneath the gloves Subaru continually wears on the direction of his grandmother, the previous family head, who recognized the marks and so hopes to conceal them with her magic.
Things come to a head when Seishirō loses an eye protecting Subaru, and Subaru realizes that he is in love with Seishirō. But the year is over, and Seishirō declares himself the winner of the bet. He breaks Subaru's arm and tortures him, but does not succeed in killing him, as Subaru's grandmother breaks his spell - an action which leaves her crippled. Subaru's shock and heartbreak leave him catatonic. Hokuto, feeling guilty for her promotion of Seishirō, whom she knew to be dangerous, but also believed to be the only one who might touch Subaru's heart, leaves to find Seishirō and confronts him, asking to be killed by him and casting a spell with her death. Subaru, seeing her in a dream, is shocked out of his catatonia by her action. He vows to find Seishirō and take revenge for his sister's death.
Subaru and Seishirō return in Clamp's apocalyptic manga X. The story, set nine years after the end of Tokyo Babylon, has the two onmyōji on opposite sides during the final battle for humanity's future.