When Quagmire recovers from his "accident" he learns that his sister Brenda needs his help.
When Peter hits his head and suffers amnesia after getting in a fight with Richard Dawson on Family Feud, he forgets everything about his life, including his family and friends. In an attempt to try to bring back his memory, Lois decides to reintroduce Peter to his old self, until he begins to hit on other women, much to Lois's dismay. She decides to take the kids and leave Peter, giving Quagmire the opportunity to score with Lois. Peter now must prove to Lois he can remember her and make himself worthy of her again.
When Peter makes it through a bad flu season without getting sick, the hospital asks him to volunteer as a nurse, but he finds himself at a crossroads when his mortal enemy, The Giant Chicken, is admitted to the ER. Meanwhile, Brian receives his genetic test results and learns he is part cat, causing him to have an identity crisis.
Eight-year-old Brian (who is 56 in dog years) seems to have lost a step or two, so Peter gets a new talking dog, New Brian, to "take some of the load off" the old one, who doesn't like the idea at all.
Peter imagines his friends and family in three of Stephen King's most famous works. Stand by Me parody - Twelve-year old Peter, Quagmire, Cleveland and Joe travel along a railroad track on a journey of self-discovery. Misery parody - Brian is injured in a bad car crash only to be "rescued" by his "number one fan," Stewie. The Shawshank Redemption parody - Cleveland and Peter become fast friends in prison.
Peter’s sister, Karen, decides to come for Thanksgiving and bullies Peter the same way Meg treats him. While Meg is at first amused, she later feels badly and decides to help Peter train to defeat his sister in a wrestling match. Meanwhile, to avoid overeating on Thanksgiving, Stewie and Brian decide to go on a cleanse, which Stewie takes one step too far.
The guys go to an abandoned asylum seeking inspiration for a new horror movie idea, but end up accidentally killing a man they think is keeping them hostage. Wracked with guilt, they each try to pin the murder on someone else. Meanwhile, Stewie is on a mission to destroy Brian's glasses because he's annoyed by how pretentious Brian's been acting when he wears them.
In the 150th episode, Brian & Stewie get locked in a bank vault, they are forced to deal with each other on a whole new level. Unlike any other FAMILY GUY episode, the acts will play out in real time as Brian and Stewie react to being locked in a small space with no baby food or martinis to keep them from losing their minds while they hatch an escape plan.