The book begins with Gary Soneji breaking into Alex Cross' home in Washington DC and contemplating the murders of Cross and his family.
In London the killer dubbed Mr. Smith by the press is conducting a live autopsy. Mr. Smith explains to his victim what he will be feeling and that he envies his victim.
At union station, Soneji opens fire on the crowd with a rifle. Cross and Sampson receive a call from Soneji letting him know where he is. Cross was expecting Kyle Craig, who had faxed Cross a letter asking for help with the Mr. Smith case. When Sampson and Cross get there, four people have already been killed. Cross and Sampson find the rifle and discover that it had been set up on a timer to randomly shoot downward. Soneji was actually on a train headed to New York City.
Soneji is at Penn Station in New York City. There, he stabs a man in the back with a big hunting knife he used to kill Roger Graham in Along Came a Spider . Soneji then escapes in a subway.
Cross is driving by the school and stops when he sees his girlfriend Christine’s car. When she gets home, they go for a walk, and Christine confesses that she worries about him getting hurt or killed in the line of duty. The two begin to kiss passionately, but are interrupted by Cross' pager.
Cross has been called by an NYPD detective, Manning Goldman, who is investigating the Penn Station murder. Goldman is sure that Soneji behind it. Once in New York City, Cross meets with Goldman at Penn Station. A total of three people have been stabbed with a knife laced with poison.
The next day Cross takes his cat, Rosie, to Quantico to be examined by the FBI. Cross is afraid that Soneji did something to the cat before giving her to him. He also meets with Kyle, who wants Cross involved in the Mr. Smith case but Alex refuses. Cross agrees to see Agent Thomas Pierce, whose own girlfriend was one of Mr. Smith's victims. Afterwards, Alex checks on Rosie, who had nothing wrong with her.
In London, Mr. Smith calls the police a few blocks down telling them where to find Inspector Drew Cabot's body.
Thomas Pierce is in London. He works on the Mr. Smith case almost exclusively. He’s trying to figure out the message Mr. Smith is trying to send.
Sampson and Cross are in Wilmington, Delaware. They are going to visit Soneji’s wife and daughter. Cross smells decay and sees flies. They find the decapitated body of a Labrador Retriever. They discover that Soneji had decapitated his wife, but spared their daughter.
Later, Cross goes to Lorton prison, where Soneji had been kept during Along Came a Spider . Cross was there to meet with a prisoner named Jamal Autry who told Cross that Soneji was raped in prison and contracted AIDS. Cross now understands that Soneji is planning one final rampage before he dies.
In New York City, Soneji quietly breaks into Manning Goldman’s house at night, and hits him over the head with a lead pipe.
Kyle Craig lends Alex use of the FBI helicopter to make his way to NYC. Cross meets with Goldman’s partner. They make their way to Goldman’s home in Riverdale. In the bedroom there is blood everywhere. The blood was splattered on the bed, the walls, and the floor. This was a brutal attack.
Elsewhere in a bar, Soneji pick up a woman and goes with her to her apartment.
Alex and the NYPD think Soneji is going after the man that raped him in prison, Shareef Thomas. They find Shareef in Brooklyn inside a crack house. A struggle ensues as they try to arrest Thomas, and Cross shoots and kills him.
In Paris, Mr. Smith attacks and kills a young doctor who had just left his girlfriends house.
At Bellevue Hospital, Soneji goes to find Thomas, who he believes is in intensive care. Soneji is dressed as a male nurse and wearing another disguise. Soneji goes into the room, only to find Cross and Detective Groza, Goldman’s partner, waiting for him in the room. Soneji is impressed, but prepared, as he throws a small Incendiary bomb at the detectives. Cross and Groza pull the bed on them to shelter themselves from the brunt of the bomb. Soneji makes his way out of the hospital and escapes in a city bus. Cross is afraid that Soneji plans on blowing up the bus.
Cross thinks Soneji is trying to reach Grand Central Station, which proves to be correct, when Soneji makes his way out of the bus and runs toward it carrying a baby in his arm. Groza and Cross follow Soneji. They corner Soneji who swears that Cross will pay for everything. Soneji gets away by throwing the baby. The baby is caught but while everyone looks at the baby on the air Soneji makes a run for the tunnels. Groza and Cross pursue Soneji again. Soneji attacks Groza from behind. Alex and Soneji fight. Soneji swears that he'll go after Cross, even if he dies. Cross shoots Soneji in the jaw. The madman falls to the ground, accidentally detonating the other bomb in his pocket, burning him.
A few days later, Cross returns home. He spends the entire day with his family. Kyle Craig calls Cross and again asks for help on the Mr. Smith case. Cross says no.
Alex's family throws him a party. That night, an unknown assailant attacks Cross and his family, beating them and shooting him; Cross believes that it was Soneji.
Agent Thomas Pierce examines the scene and wonders why the kids were left to live. He deduces they were beaten to make a statement but killing them was not the plan. Pierce concludes that Soneji is innocent of the attacks.
Pierce examines the room and notices all the blood in the room. Soon he is told Cross has gone into cardiac arrest due to loss of blood. Kyle and Thomas head to St. Anthony’s Hospital. Thomas reminisces about his days in medical school and his girlfriend, Isabella, who was murdered by Mr. Smith. Traumatized, Pierce had given up medicine.
Back in Paris, Inspector Rene Faulk investigates the young surgeon's disappearance.
After looking and analyzing evidence at Cross's home, Pierce is sure that Soneji was not Cross' attacker. Pierce finds Cross' shield, burned and charred.
Sampson and Pierce head to Princeton, New Jersey to examine the area where Soneji was raised. They went to talk with Soneji’s grandfather, Walter Murphy. They dig in the back and find human and animal bones, which had apparently been Soneji's first victims.
At the hotel, Pierce gets an e mail from Mr. Smith that he took a young surgeon in Pierce’s honor. Mr. Smith has been contacting Pierce before he commits a murder and challenges Pierce to stop him. Pierce needs to go. Sampson is not happy with it.
Mr. Smith named himself after Valentine Michael Smith from the book Stranger in a Strange Land . Mr. Smith does another live autopsy on Abel Sante.
On the way to Paris, Pierce reviews notes and tries to determine what kind of a person Mr. Smith really is. Upon reaching Paris and checking into a hotel, Pierce reads his e mail from Mr. Smith and tells him where to find the doctor’s body. Pierce is accompanied by an Interpol agent named Sandy Greenberg. In the email, Mr. Smith tells Pierce not to trust her.
Pierce recovers Dr. Sante’s body. His head had been separated from the body and the head had been cut in half.
Pierce is at the Cross house. He’s examining Cross' room and is convinced that Soneji had a partner. Pierce takes Sampson with him to Princeton and to meet a childhood friend of Soneji’s, Simon Conklin. Pierce thinks he’s the one that tried to kill Cross, but Conklin has an alibi. After interviewing Conklin, Pierce is not only convinced Conklin did it, but that Soneji had been taking orders from him.
Pierce breaks in to Conklin’s house. Pierce can’t find evidence that Conklin tried to kill Alex but after viewing the house is now sure Conklin is the killer.
The book resumes going to Alex’s point of view. He is addressing a group of FBI agents at Quantico. It is revealed that the attack was not as severe as everyone was led to believe. Craig convinced Alex to pretend to be more severely injured in order to get Pierce involved, who is none other than Mr. Smith. Pierce had actuallykilled his girlfriend when he caught her cheating on him with another doctor. The resulting trauma created in Pierce a split personality, with the "Mr. Smith" becoming more and more dominant. The authorities only have circumstantial evidence. The FBI is hoping that being involved in this case will let Pierce go after Conklin and let the FBI catch him in the act. Sara Greenberg tells the agent that Pierce was spotted at all the recent murders.
Agents are outside Conklin’s house. Inside, Pierce begins a live autopsy on Conklin, but first is trying to get a confession from Conklin for attacking Dr. Cross.
The agents go in, but it’s too late. Conklin is dead and Mr. Smith has escaped. Before dying, Conklin had confessed to trying to kill Cross.
Cross offers to go to Boston, Massachusetts to look at Pierce’s apartment. The apartment is full of pictures of Pierce’s dead girlfriend. Cross receives a voicemail from Pierce telling Cross where to find Smith’s next victim.
The victim is found but all the organs were removed.
Mr. Smith later kills a prostitute.
Cross returns home and tries to find a connection. He writes the name of the victim in order and finds the connection. It was in the names. It spelled i-m-u-r-d-e-r-e-d-i-s-a-b-e-l-l-a-c-a-l-a-i-s. (I murdered Isabella Calais). The s in Calais had not been completed. Alex knew the last victim would be Dr. Straw, the man Isabella was having the affair with.
The FBI set up another stakeout. Pierce shows up but keeps going in his car. Cross goes after Pierce and go on a high speed chase. The cars eventually go on a side road. Pierce loses Cross for a few minutes. When Cross and Sampson find Pierce’s car, Pierce is gone. Alex knows he wants to complete the puzzle. The S for Smith. Cross returns to Boston. At the apartment Smith had done a self autopsy. Alex tries to stop Pierce from killing himself and the two end up fighting. Sampson shoots Pierce, pointblank.