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.
An ant-sized arsonist named Jerry flees Mark's custody, escaping up Twayne's nostril. A miniaturized Leonard, Grimes and Mark must track Jerry through Twayne's body to bring him to justice.
Callie reveals to Mark that she's been sleeping with other guys. So when Mark's college girlfriend (Jenny Slate) shows up, he decides to put his newly "open relationship" with Callie to the test.
Twayne throws a company party aboard a cruise ship, where Randall is introduced to a strange plant species. Randall gets sick from its dangerous pollen, and finds that Mark holds the key to his survival.