Kiss the Girls begins in 1975 Boca Raton, Florida where the boy, Casanova, is killing his first four victims. Elsewhere in 1981 Chapel Hill, North Carolina a young Gentleman Caller kills his first two victims.
Present time - Casanova takes a girl to the woods and leaves her to die. He wears a mask for death. An ongoing theme is that Casanova wears a mask to symbolize his mood.
Alex Cross comes home to find his sister, grandmother, and other relatives waiting for him and is informed that his niece, Naomi "Scootchie" Cross a student atDuke University in Durham, North Carolina, is missing.
In North Carolina Sampson and Cross meet Detectives Nick Ruskin and Davey Sikes who tell Cross that the FBI and DEA are involved and that eight to ten women are missing, all from different states, all have received notes from someone calling himself Casanova.
Casanova picks Kate McTiernan for his next victim and kidnaps her. Kate awakens finding some of her things and Casanova who explains the rules and warning her not to break them. The next time he shows up to be with Kate, she fights back and he knocks her out, afterwards she awakens to find at least six other women locked in rooms near her.
In Los Angeles, reporter Beth Lieberman is working on a serial killer story about “The Gentleman Caller” who has just murdered a 14 year old girl. He threatens “bonus kills" to her if his letters are not published. Kyle Craig meets Beth in LA.
Casanova plans to kill Kate because she had broken the rules, but she fights him and gets away. Kate manages to escape, running outside into a forest and jumping off a cliff into the river below. Cross and Ruskin find out she is alive, but she is too hurt to talk
In North Carolina, Cross reads about the “Gentleman Caller” in the FBI serial killer files and one of the notes published in the LA Times mentions a black 2nd year law student, Naomi C. Cross. Alex tries to call Beth, but she hangs up on him. Cross calls her editor in chief who reveals that Casanova and the Gentleman Caller are communicating as coast to coast serial killers. Casanova calls the "Gentleman Caller."
Cross discovers Kate was drugged with sistol, which leads them to believe that Casanova is a doctor or pharmacist. Kyle tells Cross and Kate that Beth Lieberman was murdered by the Gentleman Caller, who cut off her fingers. In her computer was a suspect for Casanova, a Dr. William Rudolph from Los Angeles. Kate and Alex go with Kyle to LA.
Kate takes one look at Rudolph and is positive he is Casanova. Cross knows for sure that there are two killers which means that Rudolph is the Gentleman Caller. They follow Rudolph but he gets away from the authorities. They eventually catch up with him again the next afternoon. Rudolph has taken another woman and that night after hearing her scream, authorities rushes in, but Rudolph escapes. His apartment is searched and a picture of Rudolph with Dr. Wick Sachs from Durham is found. On the back it reads "Casanova".
Cross and Sampson discus a theory that the girls are being held in an underground house, built in an area that may have been part of the Underground Railroad. Sachs was a professor at Duke and Dean Lowell confirms Sachs was the campus skeleton, known as doctor dirt. Lowell also lets Cross know that Sachs had been a suspect when two students were murdered in the early 1980s. Later Ruskin and Sikes ask Cross for help in catching Casanova, who they believe to be Sachs.
Rudolph prowls Durham reminiscing. He met Casanova at Duke and Casanova had known Rudolph had killed the young couple and kept the woman's tongue as a souvenir. Casanova shares with Rudolph his own experiences and the two form a bond. And they both decide to work together to take down Cross, the homicide detective who was searching for both Casanova and The Gentleman Caller.
Rudolph heads to Kate's house when he sees Cross and Sampson. After they leave, Kate goes to bed, and is attacked by both Casanova and the Gentleman Caller at the same time. She is seriously wounded and taken to the hospital. Cross, Sampson, and the FBI are at her house. Cross notices that this attack was different from the first one and suspects both men worked together on this. The next day Sachs is brought in for questioning. Cross attacks him noticing that Sachs is not very physically strong and is sure that Sachs is not Casanova. Later the FBI arrests Sachs believing he is Casanova after find physical evidence pointing to him.
Sampson and Cross head to the forest again taking a hand-written map given to them by an Underground Railroad historian and Duke professor. On it is an area not already searched. As they walk, they hear women screaming. Following the screams they find the underground house.
Outside, Casanova and the Gentlemen have been watching Sampson and Cross. They plan to take out Sampson first and then Cross. Cross finds Naomi but hears Sampson scream. He runs out to see Casanova and the Gentleman, both wearing masks, on top of his partner. Sampson has a knife stuck in his back. Cross takes his gun and fires, hitting one in the shoulder. The two take off running and make it to a nearby bar, steal a truck and take off. Cross takes a car and goes after them. In traffic the two run out of the car, running on opposite directions and firing their guns. Cross follows one, they exchange gunfire, and he hits him in the chest. Cross runs to the man and takes off his mask. It is Rudolph. He dies telling Cross he would never catch Casanova.
In the underground house, Cross looks for clues and thinks he knows who Casanova is. He keeps the information from Kyle Craig and decides to go on his own stakeout. He follows Davey Sikes, positive that he is Casanova. He thinks Sikes was looking for a new woman to kidnap. Cross snoops outside a house where Sikes had gone in. Sikes sees him and the two get into a fight. The woman was Sikes’s mistress and the FBI had known about the affair.
Later, while visiting Kate, Alex goes jogging and finds a dead FBI agent. He runs back to the house where Casanova, who is Detective Nick Ruskin, hits him with a stun gun. With Cross down, Casanova heads for Kate, but Kate fights him and takes him down. He takes out his gun to shoot Kate but Cross gets up and shoots him dead.