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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.

While investigating the mystery of the black kakugane, Kazuki, Tokiko and Gouta unexpectedly meet up with Alexandria and Victoria, the wife and daughter of the traitorous Victor. Alexandria and Victoria explain that a cure for the effects of the black kakugane exists, but it comes with a steep price. Now Kazuki faces a grave choice: Can he afford to pay...or will he find that he can't afford not to?