Desperate to find a new angle into the case of the Minnesota Shrike (a serial killer who targets and removes the organs of young women), FBI Special Agent Jack Crawford recruits unorthodox profiler Will Graham, whose ability to empathize completely gives him a unique insight into crime scenes. Noted psychiatrist Dr. Hannibal Lecter is also invited to assist when a copycat killer escalates the case. Originally consulted on Will’s psychological health, Hannibal delights at the chance to see, and influence, the inner workings of the FBI. Will identifies Garret Jacob Hobbs as the Shrike, but Hannibal throws the takedown awry by tipping off Hobbs. Will and Hannibal arrive at Hobbs’ house as he slaughters his own family; Will has no choice but to gun down Hobbs as he cuts his own daughter’s throat. It is Will’s first kill, and something that will haunt him, ensuring Hannibal an intriguing new patient.

The Team is called to a secluded field where a “crop” of hands were found sticking up above ground, their bodies planted in order to grow exotic fungus. Meanwhile, Will's therapy sessions with Hannibal intensify, as he tries to find respite from the disturbed minds he inhabits and hunts. Will’s unusual skills draw the attention of tabloid reporter Freddie Lounds, who publishes a sensationalist story about him on TattleCrime.com. The story leads the killer to Abigail Hobbs (the daughter of the Minnesota Shrike—episode 101—in a coma from her father's attack). It's a race against time to stop the killer from putting Abigail in the ground and making her his next fungal crop.

Jack theorizes that Abigail may have aided her father Garret Jacob Hobbs in his serial killings. There are still seven girls missing, and their families desperately seek answers. Against Dr. Alana Bloom's advice but at Hannibal's behest, they escort Abigail back to Minnesota, where she discovers violent hostility against her and her family. Things go from bad to worse when a copycat killer murders Abigail's best friend. The evidence seems to point to Nick Boyle, the brother of an earlier Shrike victim (episode 101). An angry and violent Nick confronts Abigail, and she accidentally kills him. Hannibal suggests to Abigail that they hide the body to protect her—no one, particularly Jack, would believe Abigail acted in self-defense. But secrets come at a cost…

A massacred family is discovered seated at a perfectly-set dinner table. Jack notes that the family’s son was abducted not long ago; could the murder be an extension of that? The answer is yes, but not in the way anyone imagined… the murderer is the abducted child, returning in an act of vengeance.  In his brainwashed mind, the child's family didn't love him; otherwise, they would have tried harder to rescue him from his captor. Will deduces that the abductor is a woman attempting to build her own family, manipulating the children she kidnaps to turn against their biological parents. In the midst of this, Hannibal works with Abigail to come to terms with her own broken, lost family.

Jack, Will, and the Team are called in to investigate a truly disturbing scene—two victims with the skin on their backs cut and tied to the ceiling to mimic angel wings. The killer suffers from a brain tumor, and as more victims surface, Hannibal hypothesizes the tumor is causing violent hallucinations; perhaps he isn't creating his “angels” as symbols of worship but rather as figures of protection. The question is, protection from what? As the hunt continues, Jack must juggle the investigation with the realization that his wife has terminal cancer.

Dr. Frederick Chilton, the administrator of the Baltimore State Hospital for the Criminally Insane, asks the FBI for help after an inmate, Dr. Abel Gideon, kills one of his nursing staff and claims to be the Chesapeake Ripper. Both Will and Jack doubt Gideon’s assertions, yet he possesses information that only the Ripper could know. In the midst of their investigation, Jack is haunted by the memory of an old student at the academy, Miriam Lass, who disappeared while on the Ripper's trail.