Brian takes a job on the police force as a drug-sniffing dog, which leads him down a path of cocaine addiction. Trying to kick the habit, Brian checks into a clinic. With the Griffin family cruise canceled due to Brian’s absence, Peter gets the idea to vacation at the rehab retreat.
The Griffin family learns Brain has gone to Hollywood. After trying out on Kids Say the Darndest Things, Stewie awarded an appearance, and the Griffin get a free trip to Los Angeles. Brian doesn't want the family to know what he's really doing in Hollywood, and tries to cover it up.
When Peter's toy company is bought out by the Eldorado Cigarette Company, the toys are used to market cigarettes to children. On Lois's advice, Peter confronts his new bosses about their evil use of toys and is unexpectedly made the CEO and dispatched to congress to convince them not to pass an anti-smoking bill.
When a hurricane strikes Quohog, everything is destroyed including The Drunken Clam, which is bought out by a Brit who turns it into an English pub. As it happens, pub owner Nigel Pinchley and his family move in next door to the Griffins, and Stewie tries to teach Nigel's Cockney-accented 3-year-old daughter how to speak proper English.
Peter feels jealous when he finds out Chris has a larger penis than he does, so he tries various tactics like buying a new car and joining a gun club. He then takes Chris on a father-son hunting trip only for Chris to eventually save the day.
Meanwhile, Meg finds herself to be a target of abuse from the cool kids at school when she joins the flag girl squad.
Peter sneaks away on his and Lois' anniversary to play golf at an upscale country club, only to be struck by lightning and have a near-death experience. Death promises to give Peter a revelation to help his marriage if Peter helps him get a date.
Meanwhile, Peter sets up a fake scavenger hunt for Lois and the kids, which takes them all over Quahog.
Bonnie convinces Lois to join her Tae-Jitsu class and Quahog is invaded by New York "leafers" coming to look at the pretty colored leaves in fall. Lois quickly becomes a black-belt, and Peter uses his new dangerous wife to drive away all the annoying New Yorkers. However, Lois' new-found violent side finds its way into the Griffin household, and after trying counseling, the whole family has an all-out brawl to get it out of their system.
When Meg, due to her crush on Tom Tucker, the newscaster, applies for an internship at the local television station and gets the job, she is disappointed to find that her news partner is the most reviled nerd in school, Neil. Caught in a life-threatening news situation, Meg laments that she never had a first kiss and agrees to kiss Neil only to find that he taped the whole thing in order to broadcast it across the world. Meg broadcasts her own news that she has no interest in Neil, sending him to the ledge on top of Town Hall. She breaks his fall, only to find out that he had no intention of jumping and was just trying to get her attention again. Stewie's prized new tricycle is stolen by the neighborhood bully, but the bully soon learns not to screw with Stewie.
Peter's boss comes to dinner at the Griffin house but soon dies. The Happy-Go-Lucky Toy Factory is turned into the Happy-Go-Lucky Terminal Disease Institute. Unemployed, Peter begins his search for a job and ends up going after his lifelong dream of becoming a knight at a traveling Renaissance Fair. Caught in a compromising position with the infamous Black Knight's wench, he must defend his family's honor in an duel with the Black Knight.
Peter, Still out of a job, and now severely obese, decides to take on a new profession: Fishing. After buying a boat at a police auction, he soon finds himself in debt to a loan shark. When Peter hears of a legendary fish that, when caught, could win him the money he needs, he and the guys go searching for the mystical creature called 'Daggermouth'. Meanwhile, Lois tries to cheer up Meg with a spring break trip, where Lois is the one getting all the attention.
Peter goes with Lois to visit her sister Carole, who is now pregnant, but alone since her husband walked out on her. Carole goes into labor and Peter helps deliver the baby. Caught up in the moment, Peter and Lois decide that they want another baby. Stewie however, does not agree. Stewie does everything possible to keep Peter and Lois away from each other, but when he is locked out of their room, he is forced to take desperate measures. Stewie ends up shrinking himself down to microscopic size and seeking out his sperm-brother inside Peter's body. Instead of trying to kill his unborn brother Stewie and him unite to destroy Lois.
Chris chooses a robber out of a lineup, but after Peter accidentally tells the robber where the family lives, the Griffins are placed in the witness protection program. They are sent to the Deep South, where Chris makes a new friend, Sam. Peter questions the truth of a Civil War reenactment that showed the South winning the war, leading to Sam's father forbidding Sam from seeing Chris. Upset, Sam runs away with Chris and kisses him on the mouth. Chris tells Sam that he doesn't like boys and doesn't like him in a physical sense. The FBI agents guarding the Griffin house in Quahog accidentally tell the robber the location of the Griffins. Sam reveals to Chris that she is not a boy, but a girl. Then the robber arrives in the South, about to kill Chris, but the towns folk stop him just in time.
Peter and Lois go to the Pewterschmidts for the weekend, bringing Brian along. Brian, meanwhile, has some "issues" of his own to work out. Find out if Brian's future is to make puppies or become "less" than he is.
While trying to teach Chris about his Irish roots, Peter stumbles upon Nate Griffin, a black man in his family tree. Peter tries to embrace his new-found heritage, but can’t quite get the hang of it. When Lois’ father, Carter Pewtershmidt, sits the Griffin kids down for a look at his family genealogy, a dark secret is uncovered.
Joe gets discouraged, losing his self-confidence, after he loses a thief in a chase. Peter wants to help Joe get back to his old self so he volunteers to help train him for the decathlon at the Olympics for handicapped athletes. Peter puts steroids into Joe's drink, pushing Joe on to victory. Meanwhile, Stewie, Meg, and Brian fight over $26.
Christmas comes to Quahog! While Lois attempt to make the holidays perfect for the Griffin family, Peter messes it up. Meanwhile, Stewie learns of Santa Claus’ ability to keep 24-hour surveillance on all the world’s children.
When Brian is arrested for drunk driving, he's forced to do community service, which consists of helping Pearl, a middle-aged, agoraphobic, bitter woman. Meanwhile, Peter grows a beard and learns that a swallow has nested inside it.
When Brian auditions for a role at the local theatre, Stewie is 'discovered' and enters the Quahog School of Performing Arts. Meanwhile, Peter rescues a man from the ocean only to discover that the man is a naturist.
Lois runs into an old male friend from school and they renew their friendship, but Peter's jealousy forces a trial separation. Meanwhile, Brian and Stewie get themselves stuck together with industrial-strength glue.
Stewie is addicted to the British children's show "Jolly Farm Review" based on Mother Maggie, a benevolent figure who looks after kids on a farm. They stow away on a plane they think is bound for England. They are wrong, and soon they are in Saudi Arabia at the beginning of a long, strange trip back home. Back in the US, Peter and Lois have an odd encounter with the band Kiss.
Three stories inspired by viewers' letters: Peter loses his bones, the Griffins gain superpowers, and Peter and his friends appear as Little Rascals.
The day that Peter buys volcano insurance is the day that Lois becomes fed up with their constant money problems. When Peter wishes for a Jewish "money guy" to help them, Max Weinstein comes to the rescue. After meeting Max, Peter decides Chris could be successful if he converted to Judaism as soon as possible, but the plans for a "quickie" bar mitzvah in Las Vegas are quickly foiled by Lois.