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Yuki Cross earliest memory is of being attacked by an insane "Level E" type vampire and saved by Kaname Kuran, a pureblood vampire for whom Yuki tries to deal with her seemingly unobtainable love for her hero. Ten years later, Yuki, along with her childhood friend, Zero Kiryu are school guardians at Cross Academy where her adoptive father, Kaien Cross is the headmaster.

The story revolves around Rin Okumura, a teenager possessing abnormal strength and endurance who, along with his younger twin brother Yukio, was raised by Father Shiro Fujimoto. Soon after Yukio departs to study at the prestigious True Cross Academy, Rin learns that he is the son of Satan, the strongest of all demons.