Cruel and Unusual is the fourth in the Kay Scarpetta series of novels by Patricia Cornwell. In this novel, Scarpetta is waiting for a death row inmate to be brought to her morgue for autopsy. Scarpetta performs a normal autopsy, finding no surprises, only to discover a short time later that someone who appears to be her dead convict is committing crimes throughout Richmond. Not only this, but Scarpetta's trusted morgue supervisor is found dead, and all evidence seems to point in Scarpetta's direction. Cruel and Unusual is a dear friend in peril, making it Patricia Cornwell at her best.

Scarpetta is not used to planning an autopsy on men who are still alive, but finds herself doing just that on the night Ronnie Joe Waddell is executed. Waddell brutally murdered a young television reporter ten years before and has received the sentence the state of Virginia felt matched the crime. Scarpetta does her job, autopsying the body and filing her report. However, a few days later while investigating the murder of a young boy found in an eerily-similar fashion to Waddell's victim, questions are raised as to the identity of the body Scarpetta autopsied.

At the same time, Scarpetta begins to notice odd behavior in her young morgue supervisor. Susan Story is several months pregnant, and Scarpetta puts her odd behavior down to hormones. However, when Scarpetta learns that Susan did not fingerprint Waddell's body, she begins to question Susan's motives. Susan also begins to have strange accidents, like breaking bottles of formaldehyde. Shortly after this odd accident, Scarpetta discovers that someone broke into her computer files, and she suspects Susan.

A body is found in what was made to look like a suicide. During the investigation, a fingerprint is found that appears to belong to Waddell. Scarpetta begins to wonder if Waddell managed to switch places with another inmate, and if it was this other man who was on her autopsy table the night of the execution. However, a discussion with Benton Wesley suggests that the murder of the young boy that was similar to Waddell's victim could not have been committed by the same person because the second murder was much more organizedand showed premeditation; whereas, Waddell's crime was an act of passion.

Scarpetta begins searching for ways to prove that Waddell died in the electric chair as the state of Virginia assumes. Finding someone who can identify the body by sight proves to be difficult, however, because Waddell gained a significant amount of weight on death row and shaved his facial hair. While buried in this investigation, Scarpetta is called out on a Christmas Day murder only to find it is her morgue supervisor. Susan Story was shot in her car while it was parked on a street miles from her home. Within hours Susan's distraught husband turns to the media and points his finger solidly in Scarpetta's direction.

Scarpetta comes under investigation by the police when her fingerprints show up on an envelope in Susan Story's house. Scarpetta is relieved of her duties with the coroner's office; however, Scarpetta continues to investigate the Waddell case. Scarpetta arranges to search the home of Waddell's victim to see if they can find a fingerprint that is unquestionably Waddell's. Scarpetta finds the fingerprint at the same time her niece is able to prove someone tampered with AFIS, the government fingerprint database that made it appear that Waddell was loose and killing again.

In an attempt to find the identity of the real killer, Scarpetta travels to Florida to retrieve some evidence Waddell left to one of the murder victims. It turns out the evidence is a briefcase Waddell took from his victim's home that belongs to Governor Joe Norring. Now Scapetta has the evidence she needs to prove Norring allowed a criminal to be released from prison in order to find the briefcase and return it to Norring before anyone else could find it. With this evidence, the case comes together and the real killer is identified. At the same time, Scarpetta is able to clear her name before a grand jury and life returns to some semblance of normalcy.