When the Griffins and other residents of Quahog are invited to visit the mansion of James Woods (guest voice Woods), the evening turns into a real murder mystery when guests end up dead and everyone scrambles to figure out who done it.
When Brian (Seth MacFarlane) learns that Rush Limbaugh (guest-voicing as himself) is going to be at the Quahog Mall for a book-signing, he decides to go down there and give him a piece of his left-wing mind. But when Rush unexpectedly comes to Brian’s rescue, Brian has a political change of heart.
After Peter (Seth MacFarlane) catches Lois’ (Alex Borstein) dad, Carter (Seth MacFarlane), having an affair, he is strong-armed into keeping a secret. But when Peter accidentally spills the beans, Lois’ mom demands a divorce, and Peter is in charge of Carter’s return to bachelorhood.
Halloween arrives on Spooner Street. Peter and Joe prepare a series of unpleasant Halloween pranks for unsuspecting family, friends, and neighbors. Stewie and Brian go trick or treating, and Meg attends her high school's Halloween dance with high hopes for the evening.
When Peter receives tickets to a boxing match as a birthday gift, he volunteers Lois (Alex Borstein) to compete. To everyone’s surprise, Lois dominates in the ring and Peter decides to become her fight promoter. Her frustration with Peter turns into motivation in the ring as the housewife turns champion.
Feeling discouraged with the progress of his writing career, Brian decides to throw in the towel until Stewie become his manager and one of his books hits the bestseller list. But when the fame goes to his head, Brian gets a wake-up call from Bill Maher (guest-voicing as himself). Meanwhile, Lois decides that she and Peter need separate beds, a decision that leaves Peter looking for a new cuddle buddy.
Stewie's favorite thing after his teddy bear, Rupert, is Christmas. So when he hears that Santa is making an appearance at the mall, he begs Brian to take him so that he can tell Santa in person what he wants for Christmas. Brian begrudgingly takes Stewie to the mall, only to get the brush-off from Santa. As a result, Stewie and Brian travel to the North Pole to find Santa and teach him a lesson in holiday cheer.
After years of drinking with the guys, Peter’s (Seth MacFarlane) love of the sauce has finally caught up with him and he needs a kidney transplant. Brian (Seth MacFarlane) offers him one of his, but will a canine kidney be compatible? Meanwhile, Meg (Mila Kunis) and Chris (Seth Green) collaborate on a poem to celebrate a very important visitor.
Lois becomes friends with Joyce Kinney, the new local news anchor, and Joyce convinces Lois to let her do a story on her as the model American housewife. The television story makes Lois look terrible, and Joyce is unapologetic, leaving Lois no choice but to right a wrong.
After a public disturbance, Peter and Brian are forced to attend a 12-step meeting to help kick their drinking problems. Unable to recognize his issue, Peter gets a visit from Death, who gives him a glimpse of what life would be like with and without "Mr. Booze" in his bloodstream.
On the search to find a new hobby, Chris meets a puppeteer named Franz, an old friend of Herbert's. Despite Herbert's warnings, Chris and Franz remain friends until Franz's checkered past is suddenly revealed.
When Bonnie (Jennifer Tilly) goes out of town, Meg (Mila Kunis) offers to check in on Joe (Patrick Warburton), but she soon becomes a little too involved and starts freaking everyone out – especially Joe. Meanwhile, Stewie (Seth MacFarlane) thinks he’s losing his edge as the toughest baby on the block, so he hooks himself up to a machine that is supposed to make him more evil than ever before.
Chris (Seth Green) and Meg (Mila Kunis) think their parents have it easy, but Peter (Seth MacFarlane) and Lois (Alex Borstein) beg to differ, so in order to teach them a lesson, they all trade roles. Chris goes to work at the brewery, and Meg runs the house. While things start off well, it’s not long until the stress of running a household and being the sole breadwinner break down Chris and Meg.
When the local dry cleaner loses Peter’s (Seth MacFarlane) favorite white shirt, he goes ballistic. Meanwhile, Brian (Seth MacFarlane) tries to score on a date with a new friend, Denise (guest voice Jessica Stroup), but ends up striking out. Instead of calling it quits on love, he decides to enlist Quagmire’s (Seth MacFarlane) help, but things get nasty when they start to compete for the affections of each other’s old flames,Cheryl Tiegs (guest-voicing as herself) and Jillian (guest voice Drew Barrymore).
When Mayor West marries Lois' sister, Carol, they move into the Griffin's house to be one big "happy" family. To make room for everyone, Stewie is bumped out of his room and takes over Chris' room, but not everyone is annoyed by the change. Peter and Mayor West bond and become best friends.
In a continuation of the unprecedented ANIMATION DOMINATION crossover event, the storm that hit Stoolbend heads straight for Quahog. To help pass the time and calm his nerves, Brian (Seth MacFarlane) consumes some questionable substances and has trouble sobering up. Meanwhile, Meg (Mila Kunis) goes off the deep end after being the butt of the joke for too long.
Stewie (Seth MacFarlane) and Brian go back in time to stop Bertram (guest voice Wallace Shawn) from killing Stewie’s ancestor, Leonardo da Vinci.
Bonnie (guest voice Jennifer Tilly) and Lois (Alex Borstein) take a little trip to Paris, but Bonnie crosses the line in the City of Love. Meanwhile, Peter (Seth MacFarlane) homeschools Chris (Seth Green) and Meg using some unorthodox teaching methods.