An unmanned American Falcon-9 rocket has broken apart in flames minutes after lifting off from Cape Canaveral in Florida.
Debris from the SpaceX vehicle tumbled out of the sky into the Atlantic Ocean.
The rocket, which had 18 straight successes prior to Sunday's flight, was in the process of sending a cargo ship to the International Space Station.
The US space agency (Nasa) says important supplies have been lost but the orbiting lab's crew is secure.
Even now, the three astronauts have sufficient stores of food, water and equipment to operate until late October, and there should be visits from Russian and Japanese freighters before then.
The problem occurred 139 seconds into the flight, just before the first-stage of the rocket was about to separate from the upper-stage, or top segment of the Falcon-9.
"The vehicle has broken up," said Nasa commentator George Diller, as TV images showed the white rocket falling to pieces.
"We appear to have had a launch vehicle failure," he added.
"There was an overpressure event in the upper-stage liquid oxygen tank," tweeted SpaceX CEO Elon Musk.
"Data suggests counterintuitive cause. That's all we can say with confidence right now. Will have more to say following a thorough fault tree analysis."
SpaceX will now lead an investigation, overseen by the Federal Aviation Administration (FAA) and Nasa, which contracts the California company commercially to resupply the station.
This means there will be no further Falcon-9 launches in the immediate future.
"Once we identify the issues we will submit that documentation to the FAA and it will be considered prior to the next flight," said SpaceX president Gwynne Shotwell.
"I don't have a timeline for that right now. It certainly isn't going to be a year - (more likely) a month or so."
Nasa had loaded SpaceX's Dragon freighter on the top of the Falcon with just over two tonnes of supplies.
These included a new docking mechanism that will be needed when future astronaut vehicles - one of them based on the robotic Dragon itself - come into service later this decade.
The agency has a second mechanism that it will be sending up shortly, but it will now also have to build a third to replace the one lost in the Atlantic.
"I think this points out the challenges and difficulties we face in spaceflight," said Nasa's associate administrator for human spaceflight, Bill Gerstenmaier.
"We are operating systems at the edge of their ability. This is a very demanding environment that requires tremendous precision and tremendous amounts of engineering skill - for hardware to perform exactly as it should."
Analysis: Jonathan Amos, BBC Science Correspondent
Rockets are very complex machines and every so often, they fail. SpaceX has built a reputation for being smart and fleet of foot, and most people would expect it to bounce back from this disappointment pretty quickly.
But Sunday's mission failure does have implications for the future running of the International Space Station.
It was already operating its supplies at less than ideal levels. This was the result of recent launch failures on two other freighter systems - the US Cygnus ship and the Russian Progress craft.
Before today, the stores on the ISS were good until October. The Russians will now have another go at re-stocking the 400km-high space lab next Friday, and there will be an enormous amount riding on that flight as a consequence.
For the moment, the partner nations still plan to raise the current three-person crew to six in July. But they will surely keep that decision under review until they can be certain there are sufficient reserves of food and water to sustain a full crew complement of astronauts in orbit.
A word also for the satellite industry. This will have its head in its hands today.
The big satellite operators effectively only have three competitive companies to put up their spacecraft - Europe's Arianespace (Ariane-5 rocket), SpaceX (Falcon-9) and International Launch Services (Proton rocket).
Already, the Proton is grounded because of yet another failure this year. And with the Falcon now under investigation, it leaves only the Ariane-5 to service the commercial launch manifest.
The satellite operators need to see all three rockets in operation and fighting for their business.