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Set in the 19th century, D.Gray-man follows the adventures of a 15-year-old exorcist named Allen Walker, whose left arm can transform into a monstrous claw and destroy creatures known as "Akuma". They were created from the souls of late people by the Millennium Earl who wishes to destroy humanity. Allen wishes to free Akumas' souls after his late guardian, Mana Walker, was resurrected by the Earl and a younger Allen destroys it. After finishing his exorcist training with General Cross Marian, Allen joins the Black Order, an organization attempting to stop the Earl. With his injured left eye, caused by Mana's Akuma, Allen can detect disguised Akuma, making him a powerful asset for the Order. He is sent to recover pieces of Innocence, a substance giving the Exorcists the ability to destroy Akuma. The Earl decides to call together the Noah Family, superhuman descendants of Noah, who can destroy Innocence. Both sides begin the search for the Heart, the most powerful piece of Innocence, which will ensure victory for the side that finds it.
In his search, the Earl begins killing the Generals, the Order's most powerful Exorcists. To protect them, the Order attempts to bring the Generals back to their headquarters. Allen and three other Exorcists are sent to find the missing General Cross, but Allen and Lenalee Lee are nearly killed during the mission. They are saved by their Innocence, causing the Earl, Bookman and Bookman's apprentice Lavi, who are chronicling the war, to believe one of them possesses the Innocence Heart.
After Allen and his allies fight the Noah in a dimension known as the Noah's Ark, Cross is found and brought back to the Order. The Order then learns that Allen is to succeed Nea, the 14th Noah, who was killed for betraying the Earl. This leads the Order to suspect that Allen might betray them. When Allen disobeys orders to destroy the Akuma of a person named Alma Karma as he sends him away alongside his fellow Exorcist Yu Kanda, he is eventually confined. The Noah frees Allen to rescue him from the Apocryphos, a sentient Innocence that guards the Heart, causing the Order to revoke Allen's rights as an Exorcist and treat him as a Noah. As a result, Allen abandons the Order but still decides to continue fighting Akumas. Both the Order and the Noah then begin searching for Allen.