The story begins when high school student Kazuki Muto is killed one night saving a mysterious girl from a monster, only to wake up in his school dorm, believing it to have been a dream; however, he soon finds out that dream wasn't a dream at all when a giant serpentine monster attacks him and his sister. Tokiko Tsumura, the girl he saved, explains that the monster is a homunculus. Kazuki had been attacked and killed by it when he was rescuing her; however, she, feeling responsible for him, revived him by placing a Kakugane medallion in his chest, serving as a replacement heart. The Kakugane, as Tokiko explains, is an alchemical device that, when activated, takes a certain form based on the Kakugane's user, forming a unique Buso Renkin. The Buso Renkin is the only thing that can destroy a homunculus monster. Using this, Kazuki creates his own Buso Renkin (the "Sunlight Heart," a huge lance). Along with Tokiko and her own Buso Renkin (the "Valkyrie Skirt," an execution scythe), Kazuki joins the fight against the homunculi and their master.

Wisteria is an orphan girl living in a corner of the British Empire at the end of the 19th century. Her life is desolate and bleak–until she encounters Marbas, a powerful but equally lonely immortal being with a furry appearance, hounded by hunters. Together, Wisteria and Marbas roam the Empire–populated by humans and human-like beasts–in search of a place where they can live together in peace.

The happy-go-lucky Michi Sonoda announces to her teammate, Sanae Takigawa, that she will quit judo for good after her final middle school tournament. This leaves Sanae in disbelief; after all, it was Michi's passion toward the sport that reeled Sanae into judo in the first place. Michi claims that a well-spent youth should be associated with things such as getting a boyfriend rather than sweaty tatami mats. However, Michi's plan to end her fledgling judo career with a bang is spoiled after experiencing an embarrassing defeat at the hands of the talented Towa Hiura. Later, her plan is further derailed when she finds out that Towa has enrolled in the same high school as herself and Sanae. With the sudden appearance of her past foe, Michi may soon realize that she still has lingering feelings for the sport of judo.

Kaname Okiura, a student of Prefectoral Umineko Shougyou High ("Umishou" for short), joined the school's swimming club in order to learn how to swim, but the club is filled with weirdos, let alone who can teach him swimming. Then, a sunny, happy-go-lucky girl named Amuro Ninagawa who transferred from Okinawa joined the club. Her extraordinary underwater speed and unorthodox swimming style (plus her personal habit of nude swimming—a powerful magnet to teenage boys) surprised every club member, especially Okiura, because she reminds him of a mermaid-like creature he saw only once in his early childhood.