Kiss the Girls is a mystery/thriller tale of obsessive kidnapping and murder. Casanova, a serial killer and kidnapper, has killed several women in the vicinity of the University of North Carolina. In addition to the girls that have been killed, several others are missing. Among the missing girls is the niece of renowned detective Alex Cross. Cross, through his connections at the FBI, is allowed to work on the case. The killer seems to have a taste for extremely beautiful women and is known for his near perfect crimes.

Casanova stalks his prey with great care and attention to detail. His most recent victim is Dr. Kate McTiernan, with whom Casanova became fixated because of her stunning looks and great intelligence. He holds her captive, along with several of his other victims, in an underground hideaway in the woods. Casanova is secretive, always wearing a mask when he meets his girls. Fearing death for breaking the house rules, Kate breaks free and returns to civilization. Kate recounts the odd phenomenon that the house of the killer disappeared after she exited. Kate and Cross meet and become fast friends.

Investigators learn of a connection between Casanova and a California serial killer calling himself the Gentleman Caller. They seem to share information. The Caller has a similar taste for beautiful women. He murders them outright, however, often retaining pieces of their anatomy. The Caller is much more brazen than Casanova, regularly communicating with and taunting the media. A break in the Caller case leads Cross and Kate to travel to Los Angeles to assist in his capture. Authorities are tantalizingly close to catching him when he makes a brazen escape. They do, however, learn his identity: he is Dr. William Rudolph, an accomplished plastic surgeon and a graduate of Duke medical school. A photograph found in his apartment seems to give away the identity of Casanova.

Back in North Carolina, the investigation focuses on Dr. Wick Sachs, a professor with a taste for odd and serious pornography. Sachs is arrested after a tip leads police to evidence from the murdered and kidnapped women in his house. Shortly after Sachs' arrest, Kate is beaten severely and left for dead by Casanova and Rudolph. This confirms Cross' suspicions that Sachs is not Casanova.

Cross and his fellow D.C. detective friend, John Sampson, continue with the investigation. Cross has a hunch that the disappearing house where Casanova keeps the girls may be an old underground structure built during slavery times as a "station" on the Underground Railroad. A local history professor prepares maps of all such underground structures in the area. While searching the local woods, Cross and Sampson find the underground dwelling and find the captive girls. Casanova and Rudolph, disguised in masks, ambush Cross and Sampson as they approach the dwelling. . Cross chases them down and fatally wounds Rudolph, but Casanova gets away.

The FBI is convinced that Casanova will never be caught because he is too good. Cross, however, doggedly continues his pursuit. He develops a theory that Casanova is actually a police officer because of his ability to commit the "perfect" crime and the fact that he fired a gun using a professional crouch. Cross pursues Detective Davey Sikes of the Durham Police Department, but learns that he is not the killer.

Cross leaves the case and returns home for a few months. At the behest of his FBI contact, he and Kate take a late-summer vacation to the Outer Banks in the hopes of setting a trap for Casanova. Their plan works—Casanova attacks. Kate and Cross team up to kill him and his identity is finally revealed: He is Detective Nick Ruskin of the Durham Police Department.