After being bullied again by Sperg, Billy asks Grim to shrink him to enter Mandy's head to steal her "nerve". After Billy swallows the raw nerve, a polyp-like organism, Mandy becomes timid and scared of everything while Billy becomes tough and mean. While Billy goes to get revenge at Sperg, Mandy enters Billy's head to recover her nerve. Mandy recovers her tough and cynical attitude without her nerve, which is successfully retrieved from Billy and banished from Endsville.

After seeing Billy, Mandy and Grim battling a strange creature, Irwin again feels rejected by Mandy. Hoss Delgado, spectral exterminator, appears to help Mandy destroy the monster. Delgado decides to have Irwin as his sidekick and train him to be "cool" to win Mandy's love. Irwin gets an attire like Delgado's, and attaches an egg beater to his right hand. Delgado releases a monster so Irwin can fight it and impress Mandy, but he is humiliated anyway. Mandy tells Irwin he is just a nerd, and Billy tries to assure him that being a nerd is not such a bad thing after all.

When Billy's parents leave for their second honeymoon, Billy is left alone at the worst possible moment, since he has invited Principal Goodvibes over to dinner so he can recommend him into Rollington Academy for the Gifted. Billy's dad suggest Billy to use Eris, the goddess of chaos, and Hoss Delgado, spectral exterminator, as his substitute parents during the dinner. The dinner is a disaster with Delgado terrorizing Goodvibes, and Eris unleashing giant alien zombie lobsters. Goodvibes forcefully recommends Billy into Rollington Academy, which, as it turns out, is actually a military school.

When Billy finds his "son" Jeff the Spider lying in his bed with "Spider Pox", he goes to Mandy for help to get rid of the giant spider. While ignoring Billy, the next morning Mandy awakens afflicted by Spider Pox too, developing four additional arms and the ability to produce spider web. Mandy's condition progresses and she completely turns into a giant spider, who captures Billy's parents and Grim. Grim tells Billy that, to cure Mandy, he must use the venom of the spider that infected her. While Billy successfully gives Mandy Jeff's venom, he also carried the virus and infected the people of the city, who have all turned into spiders.

When Grim cannot take any more abuse from Mandy, Billy tries using Grim's scythe to shrink her to mouse size. Instead of shrinking, Mandy becomes a giant and destroys Billy's house. Although Mandy enjoys being a giant for a while, there are inconveniences, as she keeps growing as time passes, and she wants to return to her normal size. Billy is the only one who can cancel the curse he put on Mandy, and he refuses to do so. Mandy grows bigger than the planet, and she finds herself in the "Realm of the Infinite" with other creatures that grow at infinite pace. Mandy starts bossing them around to please her.