Instagram co-founders Kevin Systrom and Mike Krieger have resigned as chief executive officer and chief technical officer of the photo-sharing app owned by Facebook.
The departures at Facebook's fastest-growing revenue generator come just months after the exit of Jan Koum, co-founder of Facebook-owned messaging app WhatsApp.
It leaves the social network without the developers behind two of its biggest services.
They also come at a time when Facebook's core platform is under fire for how it safeguards customer data, and while it defends against political efforts to spread false information.
Mr Systrom wrote in a blog post that he and Mr Krieger planned to take time off and explore "our curiosity and creativity again".
Their announcement came after increasingly frequent clashes with Facebook Chief Executive Mark Zuckerberg over the direction of Instagram, Bloomberg reported.
In a statement, Mr Zuckerberg described the two as "extraordinary product leaders".
"I've learned a lot working with them for the past six years and have really enjoyed it. I wish them all the best and I'm looking forward to seeing what they build next," Mr Zuckerberg said.
Mr Koum's departure in May led to a reshuffling of Facebook's executive ranks.
Mr Zuckerberg's ally Chris Cox, who leads product development for Facebook's main app, gained oversight of WhatsApp and Instagram, which had been given independence when Facebook bought them.
Adam Mosseri, who had overseen Facebook's news feed and spent a decade working closely with Mr Zuckerberg, became Instagram's head of product.
Mr Systrom and Mr Krieger notified the photo-sharing app's leadership team and Facebook yesterday about their decision to leave, Instagram said. Their departure would be soon, it said.
The New York Times first reported the move.
The pair met through Stanford University and worked separately in Silicon Valley before forming Instagram in 2010.
Facebook bought Instagram in 2012 for $1 billion.
The photo-sharing app has more than one billion active monthly users and has grown by adding features such as messaging and short videos.
In 2016, it added the ability to post slideshows that disappear in 24 hours, mimicking the "stories" feature of Snap Inc's Snapchat.
The photo app's global revenue this year is likely to exceed $8 billion, showed data from advertising consults EMarketer.