The Reborn! story revolves around a boy named Tsunayoshi "Tsuna" Sawada, who is chosen to become the Vongola Family's boss due to him being the great-great-great grandson of the first Vongola boss, who had moved to Japan from Italy during his time. Also, the other candidates for the position of the head of the Vongola Family died. For these reasons, Tsuna is the only remaining heir. As such, Timoteo a.k.a. "Vongola IX," the current head of the family, sends Reborn, an infant hitman from Italy, to train Tsuna. Tsuna then unwillingly undergoes training from Reborn. Reborn's main method of teaching Tsuna is the "Dying Will Bullet" ("Deathperation Shot" in Viz Media's translation of the manga), which will make the person be "reborn" with a stronger self intent on fulfilling his dying will. Through his experiences, Tsuna unconsciously becomes stronger and more confident, which ultimately makes him better suited as the Vongola Family's boss despite continuing to reject his Mafia inheritance.

Tsuna goes through many predicaments in his progress of becoming the Vongola boss including fighting against escaped Mafia convicts posing as Kokuyo Junior High students. Later, The Varia, a rival group of Vongola assassins, claim the right for their boss to be the true Vongola boss, and start a competition to decide it. To defeat the Varia, Reborn recruits most of Tsuna's schoolmates to become the Vongola guardians: Hayato Gokudera, a dynamite expert who wishes to be his right-hand man, Takeshi Yamamoto, a baseball player who thinks the Mafia is a game, Ryohei Sasagawa, the energetic captain of the school boxing club, and Kyoya Hibari, the deadly head prefect. Lambo, a weak infant assassin who came to kill Reborn, and Chrome Dokuro, a girl who has a mental and physical link with the criminal Mukuro Rokudo, joins them as well. After defeating the Varia, Tsuna and his friends are accidentally transported to the future where they must face the Millefiore Family, which is annihilating the Vongola.

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