Narrated from the first-person perspective of John Moore, a crime reporter for The New York Times , the novel begins on January 8, 1919, the day that Theodore Roosevelt is buried. Moore has dinner with Laszlo Kreizler, the famous alienist. Kreizler is surrounded by those he has rescued, including his black servant, Cyrus Montrose, and a boy named Stevie "Stevepipe" Taggert. (Mary Palmer, another patient and Kreizler's housekeeper, is deceased by the time of this dinner.) Together, they reminisce about their times with Roosevelt, but they focus on one moment: the spring of 1896 and their efforts to catch a serial killer on the Lower East Side of Manhattan. The novel is narrated in retrospect, with Moore commenting on the events and how they impacted later history.
At 2 AM on March 3, 1896, Moore is awakened by one of Kreizler's servants banging incessantly on his door. Stevie, a young boy whom Kreizler had saved from being institutionalized and who is dedicated to Kreizler, brings Moore to the scene of a crime that Kreizler wants Moore to see. Roosevelt, the police commissioner, is already at the scene. When Moore sees the nature of the brutal murder, he is appalled. The victim, Georgio "Gloria" Santorelli, is a 13-year-old boy who prostituted himself by dressing up as a girl; the boy's wrists are tied behind his back, and he is kneeling with his face pressed on the steel walkway where he was found. Though makeup paint and powder on his face are still intact, his eyes are gouged out, his right hand is chopped off, his genitals are cut off and stuffed between his jaws, he has huge gashes across his entire body, his throat has been slashed, and his buttocks are "shorn off". The policeman at the scene, Detective Sergeant Connor, makes it clear that murders of such victims are usually ignored.
"Prior to the twentieth century, persons suffering from mental illness were thought to be 'alienated,' not only from the rest of society but from their own true natures. Those experts who studied mental pathologies were known as 'alienists'."
—"Note" at the beginning of the novel
At Roosevelt's request, Moore, Kreizler, and he meet the following morning in Roosevelt's office to discuss the case. Kreizler has examined the body and disagrees with the official coroner's report. He connects the Santorelli killing to that of a second case he knows of in which two children, Benjamin and Sofia Zweig, were killed and had their eyes gouged out. Roosevelt announces that he knows of two more murders that match the pattern. Roosevelt decides to investigate, but because Kreizler has such a dubious reputation as an alienist, and because the investigation will become politically difficult, he establishes a base of operations for them outside the police precinct. Politically, Roosevelt cannot afford to be associated with the investigation and is not involved with the day-to-day operations.
Kreizler asks for some young detectives who are open to new methods and receives the help of Sara Howard, the first woman to be hired by the police department, and Marcus and Lucius Isaacson, two Jewish brothers who were hired when Roosevelt began removing corrupt police officers from the force. The Isaacsons bring sophisticated methods, such as the Bertillon system and fingerprinting, to the investigation, although these were not popular in New York City police departments at the time nor accepted in courts of law.
The group begins to investigate the victims, hoping to understand the mind of the murderer by understanding his victims. They interview Georgio Santorelli's mother and discover, for example, that there was discord in his family. Georgio's parents had learned of his being manipulated into performing sexual acts for older boys in school, and the father's response was to try to beat it out of the boy. Georgio eventually left home and lived on the streets as a male-for-male prostitute. They also read the emerging science of psychology, such as the works of William James. Another body is discovered, and the evidence suggests that the victim knew his attacker. The team also deduces that the killer's agility on rooftops suggests that he is familiar with mountain- or rock-climbing.
Kreizler, Roosevelt, Moore, and Howard must deal with various interest groups during their investigation who wish to maintain society's status quo, including a corrupt police force, which takes bribes from owners of the brothels whose prostitutes include poor immigrants; the Catholic Church, which is wary of the potential power of an organized immigrant population; the Episcopal Church; and J.P. Morgan.