Peter convinces Brian to move in with his girlfriend Jillian and Stewie tags along to help pay the rent but he tries to interfere with their relationship. Meanwhile Meg and Chris get jobs at the convenience store where Chris befriends the manager Carl who leaves Meg to do all the work. Carl soon fires her and promotes Chris to the co-boss.

When Joe feels that his disability is holding Bonnie back from living a full life, he decides to get a leg transplant. Excited about his new ability to walk, Joe engages in extreme sports, and soon ditches his current friends, for more active ones. Peter and the guys are upset at how Joe is acting and decide to teach him a lesson.

"The Family Guy 100th Episode Special" is a special episode from the sixth season of Family Guy. The episode aired on November 4, 2007, and was followed by the actual 100th episode, "Stewie Kills Lois". It was hosted by Seth MacFarlane, who presented the funniest clips of all 99 previous episodes. This is also the only episode to credit Lacey Chabert, Meg's voice artist in the first production season, who was not credited in earlier episodes due to a contractual agreement.

Lois and Peter sail off on a cruise. Jealous that he was left behind, Stewie's matricidal tendencies are rekindled. When Brian challenges him to actually do it, Stewie carries out his diabolical plan.

Presumed dead, Lois returns from the wilderness and names Stewie as her killer. On the look out for Stewie, Joe leads a manhunt around Quahog. Determined to take over the world again, Stewie auditions for the American Idol. Desperate to stop Stewie, Lois realizes what she must do.

Peter starts an anti-immigration group after being caught up in the pro-American sentiment at a Veterans' Day parade, but his tune quickly changes when he finds out he was born in Mexico. Unable to prove his citizenship, pass the naturalization test or convince investigators that his marriage to Lois is for real, he ends up working as a groundskeeper on his father-in-law's estate and leading the fight for immigrant rights.

After Quahog is hit by a flood, Meg winds up in the hospital in a coma. When she wakes up and sees a cute med student, they immediately hit it off. Overprotective of his daughter, Peter is determined to drive the med student away. That is until Meg reveals that she is pregnant.

Peter decides to grow a mustache, and after being mistaken for a fireman, ends up lending a hand when a fire breaks out at a local fast food restaurant. The owner gives him unlimited burgers as a thank you, but he eats too many and has a stroke. When Peter recovers, he vows to expose the fast-food company for what it really is, becoming friends with a genetically engineered cow along the way.

James Woods returns to seek revenge against Peter. James Woods finds Peter's wallet, which he lost at Barry Manilow concert, and procedes to steal Peter's identity, and his family. Peter decides to ruin James' career and image.

Peter and Lois's marriage hits a bit of a snag. When Brian wins the New England Rising Writer's award, the three of them head to Martha's Vineyard for a nice relaxing vacation. Peter's usual drinking habits take over, and he soon spirals out of control, as does Brian's self restraint, as he soon professes his love for Lois. Peter and Brian test their friendship over the woman of their dreams.

Brian, afraid that he may have lost his last chance at love, searches for a former flame, Tracy. To his surprise, he discovers that he is the father to her son, Dylan. Tracy decides that Brian should raise the boy, and she drops him off at the Griffin's house. When Dylan runs rough-shot in the house, Brian's attitude towards parenting doesn't settle too well with Lois and Peter.

When Peter gets a pet parrot, he begins acting like a pirate. Peter accidentally kills the bird after raising hell through all of Quahog. Meanwhile, when Brian is visiting the vet, Chris falls in love with the intern, Anna.