Jon Stewart, who turned his biting and free-wheeling humour into an unlikely source of news and analysis to host The Daily Show, will leave this year.
His departure was announced by Comedy Central president Michele Ganeless after Stewart, who has fronted the show since 1999, broke the news to the audience at a recording in New York.
"Through his unique voice and vision, The Daily Show has become a cultural touchstone for millions of fans and an unparalleled platform for political comedy that will endure for years to come," Ms Ganeless said, calling the 52-year-old host a "comic genius".
He will remain as host until later this year, she said, but did not specify his exit date or what led to his decision.
Reaction was swift from his admirers and, in some cases, likely past targets.
"Just had the honour of being the great Jon Stewart's guest (on The Daily Show), where he announced he's leaving. Emotional night," David Axelrod, former adviser to President Barack Obama, said on Twitter.
Stewart's departure represents a second big blow for Comedy Central. Another star, Stephen Colbert, left The Colbert Report last year to take over from CBS late-night host David Letterman when he retires in May.
Larry Wilmore and the new The Nightly Show replaced The Colbert Report.
The Stewart and Colbert shows created templates for a comedic form that offered laughs along with trenchant political and social satire. Authors and politicians were as common as Hollywood celebrities on the self-described "fake news" programmes.
Stewart took a several months-long hiatus in 2013 to direct Rosewater, a well-reviewed film about an Iranian-born journalist who was imprisoned for 118 days in Tehran and accused of being a spy. Comedy Central did not indicate his future plans.
Actress and comedian Mindy Kaling blamed the lure of filmdom. "I knew when Jon Stewart left to direct that movie he was gonna try something like this," she said on Twitter.
When he returned from his film-making break, Stewart played a tape of Mr Obama urging military action against Syria because of last month's poison gas attack.
"America taking military action against a Middle East regime," Stewart said. "It's like I never left."
In 2010 Stewart and Colbert drew a crowd to the Washington Mall for their Rally to Restore Sanity and/or Fear. They tackled familiar topics - the partisan gridlock in the nation's capital and the political talk show culture that encouraged it.
Stewart was credited with effectively killing one cable programme, CNN's Crossfire, when his withering criticism of its partisan squabbling hit a nerve and the network soon cancelled it.
He poked fun at politicians but spent even more time on the media establishment covering them. The most recent example was on Monday night, when he tut-tutted NBC's Brian Williams for being caught misleading the public about the danger faced covering the Iraq War.
NBC announced yesterday that Williams was being suspended as Nightly News anchor and managing editor for six months without pay.
Stewart, however, had more barbs for the reporters covering Williams, joking that finally the media was criticising someone for misleading the public during the Iraq War.