Instagram had about 30 million users in 2012, the year it was purchased by Facebook for what appeared to be an eye-watering $1bn.
Systrom and Krieger notified the photo-sharing app's leadership team and Facebook on Monday about their decision to leave, Instagram said.
"Instagram is one thousand percent better than what it started as because of the monetization skills brought by Facebook and the competition with Snapchat".
This claim was backed by another company source, who told Tech Crunch that Facebook put pressure on Systrom to help expand the social network's dwindling teenage audience - Instagram's primary demography. People still loved it, to a degree that they haven't loved Facebook for years now, if they ever did.
Mark Zuckerberg is starting to suck Facebook Inc.'s eponymous product dry as far as rapid growth is concerned. Its rapid growth and user engagement caught the eye of Facebook, which was on the lookout for any services that might threaten its dominance of the social network space. He's now head of product, and has a CV that some of Instagram's loyal users might find ominous - he was formerly in charge of Facebook's Newsfeed.
That led to a reshuffling of Facebook's executive ranks, increasing Zuckerberg's ability to influence day-to-day operations.
Instagram is growing faster than Facebook's core app. Facebook, which is running out of people in the world to add to its product, has become increasingly reliant on the photo-sharing app for its future. It's fair to say that Instagram could have died as a little start-up in Facebook's long shadow, and it definitely benefited from the discipline, infrastructure and advertising sales machine that it accessed as a semi-autonomous region inside of mother Facebook.
Instagram, meanwhile, has remained a bright spot for the company.
"I'll still be cheering WhatsApp on - just from the outside", he said at the time.
It comes after months of chaos and scandals for Facebook.
But Instagram has also been a case study in how to run a subsidiary independently - especially when its parent is mired in user-privacy problems and concerns about election interference, fake news and misinformation.
Systrom said in a statement on Monday that he and Krieger are "ready for our next chapter" that includes "building new things".