Hannibal Lecter (Anthony Hopkins) returns in his third film outing (based on the first Thomas Harris novel which introduced the character). FBI agent Will Graham (Edward Norton) has retired with his family to Florida after a near-death experience when he tracked down and captured Lecter. However, when a new serial killer, 'the tooth fairy' who kills whole families, is discovered, Graham finds himself back on the force and asking for Lecter's help. But the tooth fairy has been writing to Lecter and Lecter cannot resist playing each side off each other, to such an extent that Graham's family are to be the next victims.