South Park has always poked fun at religion. The series sprang from a short film in which Jesus and Santa Claus engaged in a martial-arts contest over the meaning of Christmas. Neither Christians, Muslims, Mormons, nor Jews have been spared the comedy's razor-edged satire.
Only last January, in the New York Daily News, Hayes was interviewed about South Park, saying "Nobody is exempted from their [creators Matt Stone and Trey Parker] humour. They're equal opportunity offenders (laughs out loud). Don't be offended by it. If you take it too seriously, you have problems."
Isaac Hayes seems to have problems. What seems to have upset him is an episode of South Park in which one of the central characters, Stan, does well in a Scientology test and is hailed as the successor to the church's founder, L Ron Hubbard.
Hayes hit No1 in the UK with his South Park single Chocolate Salty Balls
It also suggested Scientology was a lot of bogus claptrap aimed at parting vulnerable and rich people with their money. Isaac Hayes has been a Scientologist for some 13 years.
It's the end of a good run for him, though. His South Park fixture had widened a fan base that had its roots in the 1960s with his classic recordings for the legendary Stax label. His fame was crystallised with what became his signature song, the theme from the 1971 movie Shaft.
With its pulsating hi-hat cymbals and a funky wah-wah guitar, Isaac Hayes created an urban soul-brother feel that transformed black music and paved the way for artists like Barry White and Millie Jackson.
His shaven-headed, bling-laden, ghetto chic look made him a black cultural icon.
His was not an overnight success. Despite a poor background in rural Tennessee where he was raised by his maternal grandparents after both his mother and father died, he taught himself to play the piano, organ and saxophone.
His big break came in nearby Memphis when he signed for the Stax label as a session musician in 1964. Hayes took over keyboards from Booker T Jones, and his first paid sessions were with Otis Redding.
In partnership with songwriter David Porter, he was responsible for such classics as Sam and Dave's Soul Man and Hold On I'm Coming.
His own work climaxed with his 1969 album Hot Buttered Soul, described by one critic as the most important black recording since James Brown's Live at the Apollo.
It contained only four songs including an 18-minute version of Jimmy Webb's By the Time I Get to Phoenix and an extended reworking of Burt Bacharach's, Walk On By.
With his rich baritone voice, he became a staple of late-night and FM radio and was a precursor to artists like Barry White and to rap music.
Singing with former Supremes vocalist Mary Wilson in 2003
Isaac Hayes' theme for Shaft in 1971 won him an Oscar for best original song, and set the tone for numerous successive "blaxploitation" movies - the term refers to a film genre in the 1970s targeted at a US African-American audience.
In the same year, in a politically-charged era, Hayes's Black Moses album established him as a black leader, and he became actively involved in the campaign to promote black civil rights.
It was inevitable that as well as scoring films, he would act in them too. His first role came with the 1974 Truck Turner; he has since appeared in some 60 movies on TV and the big screen, the most recent being the horror flick Return to Sleepaway Camp.
Alongside his film and musical career, Isaac Hayes became increasingly involved with humanitarian causes.
The 1990s saw him travel to the west African state of Ghana to shoot a video with Barry White. It was the first of many visits there during which he helped fund a school to assist the spread of literacy.
Isaac Hayes became a black icon
He was made a Ghanaian king with the title Nene Katey Ocansey. Last year, he married a Ghanaian woman - his fourth marriage. He has 11 children and another on the way.
It was in 1993 that he became involved with Scientology and within two years had established the Isaac Hayes Foundation aimed at increasing literacy across the globe.
Among other activities, Hayes has become involved in a Scientology-related initiative to aid impoverished inner-city schools.
Aside from his charity work, he owns two restaurants and hosts a nightly five-hour radio show in Memphis.
This year, he was hospitalised for exhaustion. Leaving South Park may at least have a physical benefit.
The French actress, Eva Green, is set to star alongside Daniel Craig in the next James Bond movie, Casino Royale. The 25-year-old star of Ridley Scott's blockbuster movie Kingdom of Heaven, will play the complex British Intelligence operative Vesper
Lynd in what is expected to be a darker and grittier Bond movie than most. But she is not much taken with the designation "Bond girl". "It sounds like a bimbo or something," she says.
Stan Collymore, former Premiership footballer, aficionado of sex in car parks and the man who once publicly struck then girlfriend Ulrika Jonsson, can boast a new string to his bow - Hollywood actor. Collymore features in Basic Instinct 2: Risk Addiction, opposite Sharon Stone, with whom he shares a sex scene in a car which then plummets into the River Thames. "Working with Stan was extraordinary" said Stone, 48. "He is the loveliest, most chivalrous, most charming and most professional person."
The Treasurer of the Labour Party Jack Dromey revealed that he had no knowledge of loans made to the party by several men who were then nominated for the House of Lords. An angry Mr Dromey, husband of government minister Harriet Harman, said he was "kept in the dark" about the loans by 10 Downing Street. Mr Dromey is due deliver his report on the controversy to the party's ruling National Executive Committee next week.
Mira Markovic, widow of the former Yugoslav president, Slobodan Milosevic, missed her husband's burial in Pozarevac, 50 miles from the capital Belgrade. Dr Markovic - dubbed The Red Witch for her communist sympathies - lives in exile in Moscow and declined to travel to Serbia even though the authorities agreed to suspend an arrest warrant against her for the alleged abuse of power during the decade she and her husband led Yugoslavia.
Written by BBC News Profiles Unit's Bob Chaundy