Real-Life Relative: His sister, Rachael, also does voice-acting on his shows (the voice of Hayley on American Dad and regularly contributes additional voices to the other shows).
Screwed by the Network: Family Guy was subjected to this back in the late 1990s/early 2000s. American Dad! has been this way as well, especially ever since Family Guy was Un-Cancelled (Family Guy even has jokes about American Dad! being nigh-unknown, such as Peter referring to the show as "...whatever FOX is limping to the barn with," and in American Dad!, Brian Griffin stares at Stan and scoffs, "Do I know you?"). Amazingly, The Cleveland Show wasn't been subjected to this treatment, despite the fact that most Seth MacFarlane fans don't care much for this show — at least not until April 2013, when FOX announced that they weren't going to continue with The Cleveland Show due to low ratings and the popularity of Bob's Burgers.
Played straight in Family Guy and American Dad!, where Peter voices the father of the family (Peter Griffin and Stan Smith), the bizarre live-in guest (Brian the talking dog and Roger the alien), the next door neighbor with a sexual side (Quagmire the sex addict and Greg Corbin, a male homosexual in a committed relationship), and a news caster (Tom Tucker and, again, Greg Corbin).
Downplayed and subverted with The Cleveland Show: MacFarlane only played two characters on the show (Tim the Bear and Dr. Fist), who were later replaced with other actors (Jess Harnell played Tim the Bear during the show's final episodes and Dr. Fist was voiced by Tom Kenny in one episode and Bryan Cranston in the show's last episodes).
Parodied and deconstructed on his Saturday Night Live monologue where he states that the many vocal impressions he does are in his head all the time and a possible sign of mental illness.
What Could Have Been: Originally, MacFarlane was hired to do cartoon shorts for the FOX sketch show, MADtv, but backed out in favor of doing his own series. Had he chosen to do work for MADtv, he would have been just like Matt Groening and created Family Guy as filler for a sketch show, just like Groening did with The Simpsons for The Tracy Ullman Show.
Also, originally: The Simpsons was going to be canceled after 23 years and Seth's revival of The Flintstones was going to take its place. This fell through when MacFarlane decided to put his Flintstones revival on hiatus and The Simpsons was renewed for two more seasons in exchange for extensive budget cuts for cast and crew members in order to keep the show afloat.
Write What You Know: One of the main reasons MacFarlane chose to make Family Guy a series was the fact that, up until the late 1990s, there was little to no TV shows that took place in the New England states.