Buso Renkin is the story of teenager Kazuki Muto, who dies trying to save a girl who was being attacked by an eerie monster. The next morning, however, Kazuki is left wondering whether it was all a dream. Lo and behold, the girl, the monster, and his death are all real! The girl, Tokiko Tsumura, was actually trying to slay the homunculus (a beast that can take the form of humans, and whose main source of food is people), but Kazuki got in her way. To revive Kazuki, Tokiko replaces his heart with a kakugane, an alchemic device that allows him to summon a lance with which to fight the monsters. It turns out that Tokiko is a member of the Alchemist Warriors, an organization sworn to protect the world from the diabolical creatures. Soon, Kazuki joins Tokiko in her quest to terminate the sinister being that creates and controls the homunculus.

With less than a week to go before the homunculus lodged in Tokiko's waist reaches her brain, Kazuki and Tokiko search for the creator of the dreaded homunculi. But little do they know that the evil genius behind the human flesh-eating monsters is an eccentric, terminally ill student at Kazuki's school!