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When South Park creators Trey Parker and Matt Stone were questioned about the meanest thing ever said to them, Stone replied "When people say to me, 'God, you guys have one of the best shows on television. You and Family Guy.' That ******** hurts so bad", to which Parker agreed: "Very well said. It's such a kick in the balls."[64] Their opinions are showcased in the two-story arc "Cartoon Wars." "Cartoon Wars Part I" aired on April 5, 2006 and "Part II" a week later on April 12.

In the DVD commentary, Parker and Stone state for the record their opinions on Family Guy. They say that although they respect the show for its fans and making people laugh, and having some smart humor, they ultimately hate the show itself and have absolutely no respect for it writing-wise, namely for its overuse on "gag-humor." They compare the show's reputation among other animated shows to the way serious musicians feel about Justin Timberlake.

In the episode, fake Family Guy clips are shown depicting nonsensical cutaway jokes with no apparent relation to the plot. Three flashbacks occur and references are made to David Hasselhoff, Knight Rider, Mr. T, Captain Kirk, and Captain and Tennille in less than a minute. Between these clips, the Griffin family is shown making comments about the same subject (Peter inviting his old sweetheart over for dinner, to Lois's disapproval), as if to point out that Family Guy needs to remind its audience what the actual plot is, given that the cutaway jokes are often in no way related to the story.

Eric Cartman justifies his hatred for Family Guy using words that echo Parker and Stone.

Don't you ever, EVER compare me to Family Guy, you hear me Kyle? Compare me to Family Guy again and so help me, I will kill you where you stand! Do you have any idea what it's like? Everywhere I go: "Hey Cartman you must like Family Guy, right?" "Hey, your sense of humor reminds me of Family Guy, Cartman!" I am nothing like Family Guy! When I make jokes they are inherent to a story! Deep situational and emotional jokes based on what is relevant and has a point, not just one random interchangeable joke after another!
—Eric Cartman, Cartoon Wars Part I

"Cartoon Wars Part II" aired April 12, 2006, revealing the Family Guy writers are manatees who take "idea balls" and send them down a shaft; a jumbled collection of ideas then become a Family Guy joke (for example, balls about "Mexico", "Gary Coleman" and "date" become a joke about Peter going on a date with Coleman in Mexico).

The treatment is even-handed, and Stan Marsh and Kyle Broflovski—two of the series' more sympathetic characters—admit to being fans. The show even acknowledges the common criticism of South Park being too preachy, through a man who gives Kyle a lift, who comments, "Sure, I know it's just joke after joke, but I like that. At least it doesn't get all preachy and up its own a** with messages, you know?"

At the 2006 Comic-Con in San Diego, writers and producers of Family Guy and American Dad! admitted during a panel that they enjoyed "Cartoon Wars", and that they now refer to throwaway jokes as "Manatee Gags."[65]

During his "class day" address at Harvard University on June 7, 2006, Seth McFarlane, in character as Stewie, referred to the "Cartoon Wars" arc with the comment: "...and TV-shows that seem to think they can skate by with random jokes about giant chickens, that have absolutely nothing to do with the overall narrative. The boys at South Park are absolutely correct, those cutaways and flashbacks have nothing to do with the story. They're just there to be funny. That is a shallow indulgence that South Park is quite above, and for that I salute them."