Catherine "Cat" Crawfield, Crispin "Bones" Russell III, and their allies have faced numerous opponents, whether demonic, undead, or mortal, but the following threats have proven themselves to be a special breed of diabolical.
- Halfway to the Grave: The Human Trafficking network is a vast criminal conspiracy, run by a ruthless vampire gangster, and backed by the Governor of Ohio.
- Hennessey is a Master Vampire who functions as the ringleader of the human trafficking network. Adopting a veneer of geniality, Hennessey captures women, including drug dealers, drug addicts, vagrants, and prostitutes, forcing them into a life of vicious forced prostitution and hemophagia. Feared by subordinates and associates alike, Hennessey subjects those who would betray him to slow and painful deaths, with one informant committing suicide rather than face Hennessey's wrath. Upon discovering Cat's identity as his attempted murderer, Hennessey kills the former's grandparents and captures her mother in order to lure her into a trap alongside his nemesis, Bones. When Cat and Bones confront him, Hennessey mocks the latter for his constant pursuit over the course of many years.
- Governor Ethan Oliver is the benefactor of the human trafficking network, and a sleazy, corrupt, and ambitious figure who hides under a good reputation. Originally frequenting Hennessey's brothels in order to rape women, Oliver eventually begins colluding with Hennessey, destroying any documents relating to missing women captured by Hennessey's organization, having Hennessey traffic the destitute and disenfranchised in order to further his political career, subsequently having a hospital bombed to eliminate the rescued victims in a bid to silence them after Hennessey is eliminated. Upon being confronted by Cat, Oliver holds her at gunpoint, and boasts about his intentions to become the President of the United States, as well as to continue the process he started.
- This Side of the Grave: Apollyon, originally Malcolm Untare, leads a massive cult of ghouls in hopes of starting a species war with the vampire community, viewing vampires as inferior to ghouls. Apollyon incited hatred against vampires in the 1400s, having claimed that Joan of Arc would become the most powerful undead creature in existence if she became a crossbreed of a ghoul and a vampire. Repeating his rhetoric against Cat centuries later, Apollyon encourages his cultists to murder vampires who lie outside the protection of a Master Vampire. Furthermore, Apollyon habitually recruits younger followers in a cruel and unusual fashion, having their tongues removed before murdering them and turning them into ghouls. During the final battle, Apollyon intends to publicly execute Cat in order to consolidate his power. After being defeated in battle, Apollyon begs for undeserved mercy upon being sentenced to death for his crimes.
- One Grave at a Time: Inquisitor Heinrich Kramer is the religious zealot turned malevolent spirit who wrote the Malleus Maleficarum, a treatise on witchcraft which motivated centuries of witch hunts. A virulent misogynist in life, Kramer had raped numerous women, then burned them as witches. After dying and becoming a ghost, Kramer had tormented anyone who sensed his presence, provoking them into killing themselves. A putrid, disgusting, emaciated sadist, Kramer, upon achieving the ability to become tangible on All Hallows' Eve, seeks out an accomplice, has the pets of his prospective victims murdered, then rapes and burns his victims before murdering his accomplice. Summoned by a medium named Tyler on behalf of Cat and Bones, Kramer attacks the group, stalking and harassing Cat multiple times. During one of the confrontations where Cat, Bones, and their allies try to stop Kramer, he murders many paranormal division personnel before escaping. Targeting Cat, he captures two other women and forces Cat to allow him to capture her for a chance to free his other victims, a promise he has no intention of keeping. Kramer attempts to force himself on Cat before unsuccessfully attempting to burn her to death.
- Up from the Grave: The new director of the Paranormal Unit and his financier inflict gruesome experiments against vampires and ghouls for nefarious purposes:
- Jason Madigan, the successor to Don Williams as the Director of the Paranormal Unit, initially presents himself as a smarmy bureaucrat, but eventually shows his true colors as a cruel sadist who has experimented on thousands of ghouls and vampires in the hopes of creating a hybrid Supersoldier. To this end, Madigan had misappropriated DNA from Cat, as well as from an unidentified soldier, forcibly impregnating a human woman with the embryo, the only embryo out of a hundred to survive pregnancy. Once the child, Katie, is born, Madigan had experimented on her and subjected her to brutal conditioning, successfully turning her into a ghoul/vampire hybrid and a ruthless Child Soldier. When Cat discovers that the Paranormal Unit is missing and arranges to meet up to discuss their disappearance, Madigan leads her into an ambush before taking her to his facility, where he attempts to experiment on her. When Cat escapes, and confronts Madigan alongside the freed captives, Madigan vindictively swallows a Cyanide Pill in order to deprive Cat of the information leading to his backer.
- Richard Trove, the former White House Chief of Staff, is Madigan's shadow backer, and a power draining demon who wants to start a war between vampires and ghouls so that his own species may reign supreme once more. To this end, Trove had encouraged Madigan to perform genetic experimentation on both species, supervising the Behavioral Conditioning of the resulting test subject, Katie. When confronted by Cat and Bones, Trove taunts Cat with the knowledge that Katie is her daughter. During the final confrontation, Trove attempts to incite the ghoul population by reminding them of Apollyon's rhetoric. Trove proceeds to attempt to drain Cat of her energy, only to be stabbed in the face with a demon bone knife.
Night Huntress World
- "Devil to Pay": Xaphan is a primordial being who makes a habit of possessing people and driving them to violence. Having taken possession of Blake Turner after his previous host ran in front of a car, Xaphan regularly forces Blake to commit acts of murder, occasionally having the incidents recorded in order to taunt Blake. When the vampire Elise, along with Cat and Bones, are in the midst of bringing Blake to Mencheres, their sire, to see if they can save him, Xaphan taunts Cat using the voices of her deceased grandparents. In his first encounter with Mencheres, Xaphan refuses to leave Blake's body, preferring to inflict whatever suffering he can before the latter expires. Upon realizing that he is trapped in Blake's body, Xaphan tries to force Elise to negotiate with him, threatening to kill the vampires in addition to Blake if they trap him in the Bonneville Salt Flats as intended. After the vampires expunge Xaphan from Blake's body via hypothermia, Xaphan attacks them and demands that Blake be revived so he can repossess the latter, only to be neutralized by Mencheres.