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.

On her first day of junior high school, Mato Kuroi meets Yomi Takanashi. Though Yomi is initially taken aback by Mako's straightforward personality, the pair quickly becomes friends and begin to spend time together daily. As a sign of their friendship, Mato gives Yomi a cell phone charm—a blue star, identical to her own. However, when the two enter their second year, their relationship starts to change. Placed in a different class, Mato begins to spend more time with Yuu Koutari instead, a girl she met through the basketball team. In fact, the former best friends drift apart so much so that Mato cannot find Yomi anywhere, as if she had disappeared entirely. Elsewhere, Black★Rock Shooter is on a quest to vanquish the Dead Master. These two, while opposed, bear a connection not unlike Mato and Yomi. As their stories begin to cross, it seems Yomi's disappearance may have to do with the blue star-shaped charm and the legendary gunslinger herself.

Shiki Toono sustained a life threatening injury as a child, and due to that incident he was sent away from the Toono household and was given to a relative to be raised. Years later, when Shiki is in high school, the head of the Toono household—his father—dies, and he is ordered to move back in by his sister Akiha, who is the new head of the household. However, Shiki holds a huge secret. Ever since that injury, he has been seeing lines on objects, and only with a special pair of glasses is he able to stop seeing them. Also he is unable to remember anything well from the time before his accident. The day he moves back to the Toono household is the day he stumbles upon a woman named Arcueid Brunstud and decapitates her with one stab of his knife in a temporary fit of insanity. When she suddenly showed up beside him later alive and well, and ask him to be her bodyguard, Shiki's journey to unravel the mysteries of his past begins. (Source: ANN)

After surviving the entrance exams, Sakuta Azusagawa has finally enrolled in the same university as his girlfriend, Mai Sakurajima. He is gradually getting used to the unfamiliar environment as he attends student gatherings and makes new acquaintances. Everything seems to be going smoothly until Sakuta's friend and Sweet Bullet idol group member Uzuki Hirokawa begins acting out. With fellow Sweet Bullet member Nodoka Toyohama pleading for his help, Sakuta realizes that he has stumbled upon another case of the inexplicable Puberty Syndrome—Uzuki is feeling pressured by the sudden surge of popularity and rumors of a potential solo career. While Sakuta searches for a solution, another occurrence of Puberty Syndrome gradually emerges from the shadows.