Will Graham est un des experts-légistes les plus habiles du F.B.I. Il excelle dans l'art de reconstituer à partir d'éléments quasiment inexistants le profil d'un assassin. Mais son "sixième sens" lui a valu de frôler plusieurs fois la mort. Alors qu'il est retiré depuis trois ans, un ancien collègue, Crawford, vient le relancer pour une affaire qui s'annonce complexe : deux paisibles familles de Birminghan et Atlanta ont été, à un mois d'intervalle, sauvagement massacrées par un "tueur de la pleine lune".
Will Graham is a former FBI agent who recently retired to Florida with his wife Molly and their young son. Graham was a 'profiler'; one who profiles criminal's behavior and tries to put his mind into the minds of criminals to examine their thoughts while visiting crime scenes. Will is called out of his self-imposed retirement at the request of his former boss Jack Crawford to help the FBI catch an elusive serial killer, known to the press as the 'Tooth Fairy', who randomly kills whole families in their houses during nights of the full moon and leaves bite marks on his victims. To try to search for clues to get into the mind of the killer, Will has occasional meetings with Dr. Hannibal Lecktor, a charismatic but very dangerous imprisoned serial killer that Will captured years earlier which nearly drove him insane from the horrific encounter that nearly cost Will's life. With some help and hindrance, Will races against the clock before the next full moon when the 'Tooth Fairy' will strike again. Elsewhere, a local photographer named Francis Dollarhyde, the killer that Will is looking for, struggles to stay undetected while seeing a hope of redemption when be begins a relationship with a blind woman who is not aware of his double life.