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A human named Mark Lilly helps supernatural creatures adapt to life in New York City while managing relationships between his half-demon, half-human girlfriend, Callie, and his recently-zombified roommate, Randall Skeffington.

Mark tries to teach a werewolf and his victim a lesson in trust by relating their challenges to the early history of New York's gang fights between vampires and the Irish in the early 1900s. Meanwhile, Leonard pursues his dream of becoming a famous magician to show up his brother and Randall plots to eat Mark while he sleeps.

Special Guest Star: Bill Hader as the werewolf and William Dyer

After having intimacy issues the prior night, Callie goes baby-crazy after Mark starts fostering a demon orphan who is assigned to him when a gangster demon gets arrested for selling his baby to a human couple. Meanwhile, Twayne starts to notice some odd changes in his body and tries to push Callie into a loveless marriage in order to adopt the demon child.

While staying with Randall's parents in New Jersey (after his father fought in the Human-Zombie Civil Wars in the 1960s), Mark accidentally "outs" his roommate as a zombie. Meanwhile, Leonard (working in DOI alone on Mark's day off) tries to identify a strange new creature (a pink blob monster) who proves to be difficult to place in the workforce due to his offensive remarks.

Mark meets a pair of tree creatures who are expected to participate in a public mating ritual sanctioned by the City of New York as a festival, but when the male tree breaks up with his mate so he can enjoy a life of promiscuity, Mark must reunite the couple or the city will be overrun by the tree creature's sexually-frustrated roots. Meanwhile, Callie, driven mad from Painful Mortal Shedding (a demonic condition similar to nymphomania and PMS), assaults Mark with demands of sex while Randall's penis runs away after a day of disgusting and embarrassing sex acts.

Special Guest Stars: Kumail Nanjiani as Neel

Mark meets a human woman who wants to become a vampire like her boyfriend (in a parody of the Twilight series). Frank and his crew have to take anger management classes under Leonard, who ends up forgetting about the instruction and hunts vampires with the police. Meanwhile, the people of the city (including Frank) are being afflicted by a strange illness called "Mad Larry", a communicable disease which transforms NYC residents into Larry King clones.

Special Guest Stars: Kristen Wiig as Tristen and Fred Armisen as Larry King

After further budget cuts threaten to shut down his program, Mark struggles to find a job for a giant ape named Kong (voiced by Jack McBrayer) who has obsessive-compulsive disorder and insists on cleaning the skyscrapers he climbs, despite it being illegal for giant apes to climb buildings. Meanwhile, Callie tries to resist her sudden attraction towards Twayne during a convention, and Randall loses the lower half of his body after his top half gets hit by a bus.

Randall believes he is not a true zombie as all he does is stalk the woman who broke his heart, Krystal (who's now dating a Russian-accented cyclops after leaving him for a warlock in the pilot episode), so he joins a zombie cult. Meanwhile, Mark is forced to deal with the clingy, codependent half of an abusive worm monster, who becomes his roommate after Randall moves out, and Leonard lives out his dream of pulling off a bank robbery.

Special Guest Star: Dan Castellaneta as Xavier Gates

Mark runs into a series of problems when he volunteers to assist Leonard with issues regarding his wand; Twayne believes he has met his soulmate, who is actually Leonard's evil nemesis, and both wish to re-assassinate the zombie Abraham Lincoln, who is back in the news as Jessica Alba's new lover.

Mark and Randall agree to accompany Callie on a Halloween trip to Hell, where they spend time with her family, who plot against Mark and Randall. Meanwhile, Leonard helps a haunted house with his anger issues.

After Randall joins the cast of a sleazy reality show about hard-partying faeries (modeled after The Real World and Jersey Shore), the program's unbalanced producer becomes obsessed with Mark, who has to help out a troll who's obsessed with asking riddles.

Mark gets in over his head when he agrees to be Callie's partner in an ancient demonic ritual; Randall babysits a sexually-confused robot who once belonged to a perverted mad scientist.

Mark decides to take in a baby Man-Bird that was separated from its family, while Grimes struggles to settle a blood-feud with their champion.

Twayne is drafted into the Army of Satan. When Mark is forced to join him, he discovers a plan to end humanity.

Mark accidentally puts on an engagement ring belonging to Leonard, which helps him influence two dragons to mate, makes people take him seriously now that he has the power of influence, and sets him up to be the unwilling groom to a cryogenically-frozen bride.

Callie reveals to Mark that she's been sleeping with other guys. A girlfriend from Marks past returns, with a dark secret.

Randall feels neglected; Grimes mummy returns.

In honor of Twayne's 10-year anniversary of running the D.O.I., Callie and the crew throw him a Roast. But when Mark's attempt at edgy humor goes too far, Twayne quits, leaving Mark in charge. Before his first day as boss is up, Mark makes a management mistake so catastrophic that it almost destroys New York City.

Mark becomes conflicted about his relationship with Callie after she gets a promotion by turning herself into a man. He does his best to be understanding, but their love is soon put to the test when they are asked to embark on a dangerous mission to the fabled underwater city of Atlantis.

After being bitten by a rabid Bat-Boy, Mark becomes a masked crimefighter; Mark wages war against New York's criminals and their catlike leader with the help of his loyal sidekick, Koala Man.

Mark chooses April Fool's Day to ask Callie to take their relationship to the next level, but his romantic gesture is threatened when Callie's vengeful ex-boyfriend returns to win her back; Leonard tries to redeem a winning lottery ticket.