- Kyle Craig/The Mastermind the main antagonist of the series. He is first introduced in the earlier novels, but doesn't become an actual villain until Roses Are Red where he robs the bank and goes on a killing spree while trying to kill Cross. He is stopped by Cross in the following book Violets Are Blue and is put into prison. In Double Cross he escapes from prison and begins a new massacre while another murderer, known as DCAK begins a new reign of terror, and runs away. He gives a taunting phone call, foreshadowing his return, in I, Alex Cross and he in fact does return in Cross Fire in which he disguises himself as Max Siegel and tries to kill Alex again. He once again fails and, shortly before going to prison again, picks up an officer's gun and kills himself—as well as two officers—by shooting a gas tank. He was once a FBI agent and friend of Alex, but was later explained to have always been a murderer. He had killed his abusive father, presumably killed one of his brothers, and later killed his mother. In Violets Are Blue several things are explained about Craig: in Kiss the Girls he went to college and killed with the villains; he is presumably an atheist, believing he is second to no one; he wants to kill Alex because he wants to prove to himself that he is truly smarter than Cross—but his reason is later changed to be for ruining Kyle's life by sending him to prison. He is described as a "woman hater" despite possibly having a crush on Kate McTiernan, a main protagonist in Kiss The Girls. Craig helps Alex on several cases since the first book, and even offers Alex a job at the FBI at one point, which Alex accepts after Kyle is arrested. Kyle is briefly seen in the films Kiss The Girls and Along Came a Spider, and may appear in Double Cross (a new in the works sequel) as the character appeared in the novel. In the new novel, Double Cross, Kyle escapes from prison and murders a few people while on the loose, with his mother being one of the victims. At the end of the novel, he is still at large, despite being wounded by Alex and his girlfriend, Bree Stone. Kyle makes another full return in Cross Fire, where he takes the identity of Max Siegel by plastic surgery. He uses his new identity to gain the trust of Alex once more before revealing himself at the end of the novel. He engages in a final fight with Alex and his wife, Bree Stone, where he is wounded and arrested. Not wanting to go back to prison, Kyle kills himself by shooting an oxygen tank.
- Gary Soneji/The Son of Lindbergh the main antagonist of Along Came a Spider; he is in prison in Kiss the Girls and escapes in Jack & Jill. In the fourth book Cat and Mouse he tries to kill Cross (as well as a man who had raped him), but is defeated/killed by Cross; his friend later attacks Alex who stops him as well. While, Kyle Craig is the series' main antagonist, Soneji is Alex's deadliest adversary, and is therefore much more powerful in his own way than the "Mastermind" who is not as deadly as Soneji but is depicted as the main villain. Soneji appears in Along Came A Spider, but dies in the film—which does not happen in that novel, as he dies in Cat and Mouse. He also gave the Cross family a cat in Jack and Jill which they keep and start getting attached to it; despite Alex's initial hesitant response—thinking the cat to be rigged with a device of some sorts or some such. The cat is forever mentioned in most books. Soneji is also seen in two books; and is mentioned in several.
- DCAK standing for DC Audience Killer, brother and sister Anthony and Sandy start a killing spree, which Bree Stone is put on the case, while Alex decides to help and nicknames them 'DCAK.' They appear in Double Cross. In the book they are believed to be lovers, while brother and sister. In the novel they kidnapp Sampson—keeping him hostage—while Alex and Bree stop them. Sandy is killed while Anthony is chased in hot pursuit by Alex. He is eventually shot and defeated; while Alex learns that Kyle Craig is back and in D.C., after learning DCAK was sort of working with the Mastermind (since they 'admired him). Craig is shot and flees; at a hospital, Anthony vows revenge on Alex.
- Geoffrey Shafer/The Weasel, the antagonist of Pop Goes the Weasel and London Bridges. Shafer is responsible for kindapping Christine Johnson, Alex's fiancee at the time, and killing his own wife in Pop Goes the Weasel. He is not seen until three or four books later (London Bridges) where he works with the Wolf, a serial killer, and decides to hunt down Alex Cross, only to be fatally wounded and defeated by Cross when he confronts him. He competes with a small group of other people, known as The Horsemen to kill people, or "live their fantasies", in The Weasel. He is also known to have started killing many years before he was even introduced and has gone over 100 murders. Shafer is described as one of Alex's worst enemies.
- The Wolf, is the antagonist of both The Big Bad Wolf and London Bridges. The Wolf is considered to be the first and only super-villian that Alex Cross has ever faced in the series. He is responsible for a network of human smuggling in The Big Bad Wolf and is never caught. His identity is remained unknown until the end of London Bridges, when he returns with Geoffrey Shafer to take on Alex. The Wolf's real name is revealed to be "Anton Christyakov". The Wolf is in control of an organization that proves to be very powerful in the events of the novel. At the end of London Bridges, Anton kills himself with poison, in order to avoid the authorities. Despite Kyle Craig, Gary Soneji, and Geoffrey Shafer, The Wolf has proven to be more dangerous than any them. Being able to keep his identity safe, forcing other killers to do his bidding, and taking on world governments.
- Ron Guidice: a man who spies on Alex and posts bad things about Alex at his website, "TheRealDeal". He impregnated two women, killed both, took his daughters and spied on Alex. After a fight with Alex, his nose is broken, causing Guidice to lie and say Alex is on drugs and presses charges on Gudice. After he kills Ava, he later comes after Alex, but is shot and killed by Bree Stone.
In Alex Cross, Run Elijha Creem is the book's main antagonist, but the man who kills Ava, the newest member of the Cross family (under adoption though) is killed. Bree kills Guidice near the end of the book. The man is also considered a secondary antagonist.
Famous quotes containing the words antagonists and/or notable:
“There is a persuasion in the soul of man that he is here for cause, that he was put down in this place by the Creator to do the work for which he inspires him, that thus he is an overmatch for all antagonists that could combine against him.”
—Ralph Waldo Emerson (18031882)
“In one notable instance, where the United States Army and a hundred years of persuasion failed, a highway has succeeded. The Seminole Indians surrendered to the Tamiami Trail. From the Everglades the remnants of this race emerged, soon after the trail was built, to set up their palm-thatched villages along the road and to hoist tribal flags as a lure to passing motorists.”
—For the State of Florida, U.S. public relief program (1935-1943)