Lincoln Rhyme (DENZEL WASHINGTON) is one of New York City's leading forensics specialists with a virtual encyclopedia of knowledge in his head that he taps to solve cases. He's also suicidal due to an injury in the line of duty that's left him paralyzed and bedridden for the past four years with the use of only his head and one index finger.
Assisted by his in-house nurse, Thelma (QUEEN LATIFAH) and technical guru Richard Thompson (LELAND ORSER) who keeps his high-tech bedside computer equipment operational, Lincoln hasn't had much will to continue living. That's mainly due to progressively recurring seizures that threaten to leave him in a vegetative state, a point he uses in trying to convince Dr. Barry Lehman (JOHN BENJAMIN HICKEY) to help end his life when necessary.
Things change, however, when police officer Amelia Donaghy (ANGELINA JOLIE), who wants a desk job in the youth services division, comes across a crime scene and smartly reacts to protecting and noting evidence related to the homicide. While Captain Howard Cheney (MICHAEL ROOKER) isn't happy about a beat cop acting like a detective, Lincoln takes her under his wings after sensing that she has what it takes to be a good detective.
Thus, with the help of Lincoln's former partner, detective Paulie Sellitto (ED O'NEILL), his new partner, Kenny Solomon (MIKE McGLONE), and research scientist Eddie Ortiz (LUIS GUZMAN), Amelia quickly learns the ropes and becomes Lincoln's field presence as they investigate what turns out to be the work of a serial killer who's determined to leave clues about his next killing.