Jack and Jill by James Patterson is the third installment in Patterson's popular Alex Cross novels. In this novel, Cross finds himself torn between two serial murder cases. The first serial killer is active in Cross's own backyard, killing children who attend the Sojourner Truth School, the school Cross's own son attends. This case hits so close to home that Cross is passionately determined to solve it as quickly as possible. At the same time, however, a couple who call themselves Jack and Jill are killing high profile celebrities. The Jack and Jill case is more public, therefore the Washington DC Police Department is under greater pressure to solve the case. As one of their best homicide investigators, Cross is assigned to the case. Cross resents this reassignment, but becomes deeply engrossed in the mystery when Jack and Jill's target turns out to be the President of the United States. Jack and Jill is a fascinating novel that reveals the secrets of both sides of Washington DC society.

Cross is awakened early in the morning by his partner, Sampson, and told that a murder has taken place at the Sojourner Truth School. This murder hits too close to home because this school is the same one Cross's own son, Damon, attends. Cross begins the investigation only to have it closed within a few days when he and Sampson chase down a man they believe to be the killer. However, the man dies before it can be determined he is, in fact, the Truth School killer. Before Cross can satisfy himself that the case is closed, he is called away when Senator Fitzgerald is found murdered. A poem at the Fitzgerald crime scene reveals not one killer, but two, calling themselves Jack and Jill. The murder appears to be a celebrity stalking case with a sexual aspect, but Cross is not sure that the case is all it appears to be. Cross's confusion deepens when the killers send a video tape of the killing to CNN, seemingly taunting the police.

Cross learns of another killing in his neighborhood. It appears the Truth School killer has struck again. Cross investigates this new killing by interviewing neighbors and the principal of the Truth School, Christine Johnson. Cross finds Christine to be an intelligent and beautiful woman who could tempt him to give up his single lifestyle. Unfortunately, Christine is married and Cross is not the type of man to ignore his morals. However, Cross does not think twice about reaching out to Christine and calling her a friend.

Once again, Cross is pulled away from the Truth School killer case. A popular television news reporter is found dead in her exclusive apartment. While investigating the murder, Cross gets into a confrontation with his boss. As a result, Cross is reassigned to the task force investigating the Jack and Jill case. Cross is under pressure from his grandmother and his own conscience to solve the Truth School killings and feels that with him off the case, the case will not get the attention it needs. Therefore, Cross arranges for Sampson and few other detectives from the neighborhood to investigate the case on their own.

Two more murders are committed by Jack and Jill. First is a Hollywood actor killed in a Washington DC hotel room. The second is a young law student who turns out to be the mistress of the President of the United States. Soon the task force on the Jack and Jill investigation begin to believe President Thomas Byrnes is a target of Jack and Jill. This is confirmed when Jill calls the White House, bypassing all the security channels, and tells Byrnes he is already dead.

Cross tries to stay a step ahead of Jack and Jill. Cross works closely with the task force, including the CIA liaison, Jeanne Sterling. Sterling tells Cross that she believes one of the CIA freelance assassins might be Jack. Cross investigates this possibility and focuses on one killer in particular who might be Jack. At the same time, the Truth School killer appears to have been identified. Someone uses a Prodigy account to brag about the killings. Sampson and Cross storm the home of this account owner only to find the suspect, a thirteen-year-old-boy named Sumner Moore, is missing. However, they do find proof of the killings in his room. Unfortunately, Sumner is later found murdered.

At the same time, President Byrnes has decided he does not want to hide from Jack and Jill. President Byrnes makes the decision to attend a scheduled speech at Madison Square Garden. Cross goes on this trip as well, anxious to do all he can to protect the President. However, when the time comes, Cross is unable to stop what has already been put into motion. The President is shot and killed, as is his killer, Jack. Police also find Jill dead in a local hotel room. At the same time, the Truth School killer arrives at Christine Johnson's house and kills her husband before taking her hostage. Cross rushes back to DC in order to respond to the killer's desire to speak to him. When Cross arrives, he learns that the Truth School killer is thirteen-year-old Danny Boudreaux. Danny is a confused young man whose parents both died when he was young, leaving him struggling with a mood disorder that doctors struggle to diagnose. Danny has focused on Cross because he reminds him of his father.

Cross manages to get the gun away from Danny and save Christine Johnson. It seems both cases are over. However, while searching Jill's apartment, Cross finds a tape that reveals the identity of the real Jack. Cross and other members of the task force arrest the real Jack, who turns out to be Brett Sterling. Cross also arrests Jeanne Sterling, Brett's wife and co-conspirator. Cross hopes to learn the Sterlings motivation's for killing President Byrne, but the Sterlings are killed in prison before they can talk.