Sean Archer, a very tough, rugged FBI Agent. Who is still grieving for his dead son Michael. Archer believes that his son's killer is his sworn enemy, a very powerful criminal, Castor Troy. One day, Archer has finally cornered Castor, however, their fight has knocked out Troy cold. As Archer finally breathes easy over the capture of his enemy, he finds out that Troy has planted a bomb that will destroy the entire city of Los Angeles and all of its inhabitants. Unfortunately the only other person who knows its location is Castor's brother Pollux, and he refuses to talk. The solution, a special operation doctor that can cut off people's faces, and can place a person's face onto another person. Archer undergoes one of those surgeries to talk to Pollux. However, Castor Troy somehow regains consciousness and now wants revenge on Archer for taking his face. Not only is Troy ruining Archer's mission, but his personal life as well. Archer must stop Troy again. This time, it's personal.

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.