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.
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.
With Mark working all the time, Randall feels neglected, so he decides that they should spend more time together to decide if they should stay roommates. And Grimes's Mummy (Christine Baranski) returns from the dead, only to find fault with everything Grimes is doing.
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.