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- Channel Hop: Ran on Fox until 2014 whereupon it switched over to TBS. Bizarrely, it switched over during the run of its tenth season. The first three episode aired on Fox but from "Blonde Ambition" onwards, it was TBS.
- Hey, It's That Voice!: Stan's boss is Captain Picard!
- In one Christmas Episode, Paget Brewster guest starred as a red-haired lawyer with (eventually) wings and a quirky personality. Coincidentally, Paget used to play a red-haired lawyer with wings and a quirky personality.
- Plus, Dee Bradley Baker as Klaus.
- It's a testament to Seth MacFarlane's vocal talents that his voice doesn't leap out at you as much in this series (or The Cleveland Show, as MacFarlane's only character he voices in that series is Tim the Bear, Cleveland's next-door neighbor). Most viewers can figure out that Seth voices Stan (since the voice of Stan has been used on Family Guy in a couple of parodies of 1950s educational short films, like the one on "I Am Peter, Hear Me Roar" about how men deal with women in the workplace), but a surprisingly large number of people aren't aware he voices Roger the alien  and Greg the newscaster.
- Hayley is voiced by Rachael MacFarlane, Seth's younger sister, which leads to a lot of incestuous undertones as both Seth and Rachel have played characters who get romantically involved (Stewie Griffin and Olivia; a couple episodes of American Dad have had references to Hayley being romantically involved with her father — in "Francine's Flashback," Stan's plan of revenge after Hayley's boyfriend runs off with Francine is for Stan and Hayley to date each other [until Stan realizes that he didn't think the plan through], and "Pulling Double Booty" was all about Hayley dating a man who actually looks like Stan).
- Another incest reference: in one episode of Family Guy, Rachel played a flight attendant who got seduced by Quagmire.
- And of course Lisa "Phoebe" Kudrow as the voice of a Christmas Spirit in one episode.
- Spottswoode is Stan's dad, Jack.
- An Apocalypse to Remember has Roger trying to get married to a Jewish woman; the father of the woman is the same voice actor as Ron's Jewish father in Kim Possible.
- Dr. Cuddy plays mountain man Buckle's incredibly Jewish wife Shari.
- Sarevok took a break from trying to be a god to work as the principal at Steve's school.
- Interestingly enough, both Rachel and Dee played characters, Numbuhs 362 and 4 (another Butt Monkey) respectively, on Codename: Kids Next Door.
- It appears that in Spain and Germany, Steve is Piggley Winks. In the former country, he's also Screech and Piglet.
- Jon Kavanaugh apparently moonlights as a series of detectives in Langley Falls all named Turlington.
- Milestone Celebration:
- "100 A.D.", October 3rd 2010, celebrated the show reaching 100 episodes.
- "The Two Hundred", released on March 28th 2016, celebrated the show reaching 200 episodes.
- "300", released on September 14th 2020, celebrated the show reaching 300 episodes.
- What Could Have Been: Originally, Laura Prepon (Donna from That 70s Show) was supposed to voice Hayley Smith, but was replaced by Seth MacFarlane's sister, Rachel. Had Prepon stayed, the show would have gotten a lot more unfavorable comparisons to Family Guy as the latter show also has someone from That 70s Show as a cast member (Mila Kunis replaced an uncredited Lacy Chabert on Family Guy and played Jackie on That 70s Show).
- (though, if you watch both this show and Family Guy long enough, you can sort of tell that Seth voices Roger because Roger's crying sounds exactly like Peter Griffin's)
- and a great number of other characters, mostly goofy black guys or scary black men. Exceptions to this rule include The Joker from The Batman and Exile Mikhailovich Zanhusky