The hilarity continues this season when Brian and Stewie hit the road in search of Rupert, Stewie’s teddy bear, after he’s accidentally sold at a garage sale.
Stewie becomes obsessed with Lois after she saves Rupert, although Lois doesn't take to the "new" Stewie all too well. Meanwhile, Peter thinks his doctor is molesting him when he undergoes a prostate exam.
Peter's mom gets a divorce. Peter feels abandoned until he sees a father figure in his mom's new boyfriend, Tom Tucker. Meanwhile, Brian gets his own NPR style show on the radio.
After Peter uses Meg's money to buy himself a tank, she gets a job at the new Superstore in town. However, the Superstore puts all the shops in town out of business and sucks up the city's power supply. Brian and Stewie team up to save the town from the corporate giant.
Chris is approached to join the military. Brian goes to the recruiting headquarters to voice his opinion, when Stewie signs himself and Brian up for the military. They pass Boot Camp and are shipped to Iraq, where they try to get honorably discharged by doing anything they can. Meanwhile, Chris decides to join a goth band.
When Peter gets hurt and can't work, his boss tells him he needs to speed things up. So Lois goes to the brewery to help him out. Meanwhile, Stewie finds out that Brian is dating a very attractive but not very intelligent woman. He tries to get Brian to break up with her, but Brian can't do it.
Lois discovers that Chris has some bad information about sex and she volunteers to teach a sex-ed class at the high school. Some parents become upset with her brutal honesty, and they have her replaced. A conservative christian comes to Quahog and gets rid of the condoms at James Woods High. As a result the kids find an interesting loophole. Meanwhile Stewie, terrified of the Tooth Fairy, decides to set traps to destroy him.
Stewie ties the knot with his old flame Olivia, but their relationship quickly turns, and becomes normal dull marriage. It all escalates when they go on a double date with Brian and Jillian. Meanwhile, Lois introduces Peter to chick flicks, so he decides to make his own movie with a plot based on every chick movie ever.
Meg can't find a date to her junior prom, and even though he is dating Jillian, Brian ends up going with Meg. At the prom, Brian gets drunk to make the night pass, but ends up making out with Meg. Meg begins to think of Brian as her boyfriend and becomes obsessed with spending every moment with him. Meanwhile, Peter, Cleveland and Quagmire join the police force to help Joe, and end up saving Brian.
Brian sells Rupert at a garage sale. Stewie, who is upset with Brian, takes him cross country to Colorado to find his beloved teddy, and ends up having a ski-off to win back Rupert. Meanwhile, Peter loses his license, so Meg has to drive him around.
After Peters dad, Francis, dies, Thelma tells him that his real father actually lives in Ireland. So Peter and Brian decide to head there in search of his father, who ends up being the town drunk. They decide to play a drinking game to prove his paternity. Meanwhile, Stewie acts out and Lois spanks him. Realizing that he likes being spanked, Stewie does whatever he can to get into trouble.
When a bully harasses Chris, Peter goes to his defense, but ends up beating him up. Peter realizes bullying is fun and begins to bully everyone in the house. Finally, Chris stands up to Peter and beats him senseless. Meanwhile, Stewie goes out without sunscreen and becomes obsessed with getting a tan. After Brian leaves him in the tanning booth for six hours, Stewie gets sunburned and fears he has cancer. While waiting for the results of his cancer screening, Stewie begins to live his life as if he had only days to live and drives Brian crazy with his demands.
Quagmire takes Peter to work but Peter messes things up, causing Quagmire to lose his job as a pilot. After not being able find another job, Peter and Cleveland make plans to help him get his old job back. When the plan fails, Quagmire receives advice from his idol, Hugh Hefner.
Peter helps Bill Clinton with his flat tire, and they soon become friends. They begin spending a lot of time together and Lois begins to believe that Bill is inflicting bad influence on Peter. But when she confronts Bill, they end up having sex. Peter, upset that his wife would do this, tries to get back at Lois by having an affair of his own, but soon realizes that he loves her too much to do so. Meanwhile, Lois and Stewie try to potty-train Brian.
The Griffin family decides to start their own restaurant, though have a hard time attracting customers. After Joe promises to help, Peter is excited at the fact of it becoming a local hangout for the police. However, things don't really turn out as hoped, and instead it begins to be popular with the handicapped. When Peter attempts to change the place, a sudden twist of irony quickly changes his mind.
Lois gets a job as the church organist, so the family decides to begin going back to church. When Stewie gets sick after receiving communion, the congregation becomes convinced that he has been possessed by the devil. While on the run, the family ends up in Texas, where Peter begins to fit right in with the cowboys, Stewie enters the "Little Miss Texas" pageant, and Chris and Meg sneak into George W. Bush's house.
After Chris is expelled from school, he is sent to a boarding school that his grandfather Carter attended, but Chris doesn't exactly fit in. Meanwhile, the chicken returns to pick a fight with Peter.
Lois runs for mayor of Quahog, though she doesn't become the front-runner until she dumbs down her political views. Once in office, she becomes corrupted with the power that she now holds, and begins accepting bribes so that she can buy herself expensive things. Meanwhile, Peter comes to enjoy being the "first lady" of Quahog, and all of the perks that go along with it.
Death grants Peter's wish to go back in time to 1984 when he was 18, but only for one night. He ends up bailing on a date with Lois to hang out with a movie actress. When he returns to the present, he soon realizes that everything is anything but normal, as he is now married to the former actress, and Lois is with Quagmire. Meanwhile, Stewie, Chris and Meg have also taken on Quagmire's charming characteristics.