With the assistance of Kaname Kuran, Headmaster Kaien Cross founded Cross Academy under the influence of Juri Kuran's dream of having humans and vampires co-exist together. Kaien had mainly done this because he once made the decision to kill the Kurans, and he had stalked Juri, waiting for an opportunity to do so. He was, however, instantly defeated by her during their confrontation, and a bargain was made that he would create Cross Academy.
The fact that vampires are attending the Academy is a complete secret from the Day Class humans. They are not to know the existence of vampires, and if they do find out, their memories are erased on the spot. The existence of the vampires must be kept a secret, in Kaien Cross's mind, else humans would be too frightened to be near the Academy and animosity that would arise. Yuki Cross and Zero Kiryu are the Guardians in charge of protecting this secret.
The duty of the Guardians is to make sure the Night Class doesn't cause any trouble for the Day Class students and vice versa, and perform duties as the Headmaster requires of them. This usually entails the night patrols he assigns them (to make sure no Day Class students have snuck out of their dorms while the Night Class is in session), as well as the dawn and evening crossovers between the two classes to the main Academy building.
Unfortunately, people within the Vampire Hunter's Society and the Vampire Senate begin to interfere in the Academy's business, and two powerful Purebloods, Shizuka Hio and Rido Kuran, each come to the Academy for their own reasons.
Shizuka possessed the body of one of her young relatives, Maria Kurenai, to infiltrate the Night Class, looking for Zero , whose family she had attacked when he was a child. Her intention was to kill Kaname and steal the powers his blood contained. She was eventually discovered and killed by Kaname, and the murder was blamed on Zero. This event triggered the involvement of the Vampire Senate, who came to the academy to kill Zero for the murder of a "sacred" pureblood. They are eventually halted and destroyed by Kaname .
Rido, using his son Senri Shiki's body, infiltrated the school to find Yuki and consume her blood. He brought an army of Level E vampires with him, attacking any student without hesitation to find her. The Night Class, rallied by both their own initiative and the encouragement of Kaname, defended the school from the attacks, but the fact that they were vampires was revealed to the Day Class. Later, the Day Class votes strongly to maintain their memories of the Night Class, and are granted their request. However, after carefully interviewing the students, only some retained their memories.
After the ordeal is over and Rido is defeated, many portions of the Academy are left in rubble and ruin, and the school is shut down. However, a year later, some of the school is rebuilt and Kaien, upon Yuki's request, reinstates the Night Class after gaining the necessary support.