The Discovery orbiter has blasted away from the Kennedy Space Center - on a hot and sunny US Independence Day.
The shuttle left its Florida launch pad right on schedule at 1438 EDT (1838 GMT) and roared skywards to the cheers of spectators.
The vehicle's mission will take it to the International Space Station (ISS).
The shuttle flight is the first of 2006 and only the second since the catastrophic loss of the Columbia orbiter three years ago.
There was some concern among US space agency (Nasa) officials after several pieces of debris appeared to fall off the external fuel tank shortly after lift-off.
"About two minutes and 47 seconds, give or take, we saw three, perhaps four, pieces come off," said Wayne Hale, the shuttle programme manager.
He added that it was unclear whether the objects were insulating foam or "something else", but said it was too high to cause damage to the craft.
Tuesday's successful blast-off followed a frustrating weekend when stormy weather over Kennedy had scrubbed two attempted getaways.
When a small breakage was then found in the insulating foam on Monday, there was concern that a further delay would be ordered.
DISCOVERY SHUTTLE FLIGHT
Mission known as STS-121
Discovery's 32nd flight
18th orbiter flight to ISS
Lift-off: 1438 EDT, 4 July
Location: Kennedy Space Center, Launch Pad 39B
Objective: To test new safety equipment and procedures
Payload: Cargo bay has 12.75t of equipment and supplies
Crew: Lindsey, Kelly, Fossum, Nowak, Wilson, Sellers, Reiter
But Nasa officials said the defect posed no risk to the vehicle and cleared Discovery to go for launch.
"Discovery's ready, the weather's beautiful, America is ready to return the space shuttle to flight. So good luck and Godspeed, Discovery," launch director Mike Leinbach said just before lift-off.
"I can't think of a better place to be here on the Fourth of July," radioed back Discovery's commander Steve Lindsey.
The orbiter's seven astronauts - five men and two women - are making the 115th flight of the American shuttle programme.
They are delivering almost 13 tonnes of equipment and supplies to the ISS. One of their number - German Thomas Reiter - will be staying aboard the orbiting platform when the others leave in just under two weeks.
In addition to servicing the ISS, the mission will test safety systems introduced following the destruction of Discovery's sister ship Columbia and the deaths of its crew in February 2003.
Columbia was struck on launch by a large piece of insulation foam that punctured a hole in its left wing and left it open to the destructive superheated gases of re-entry.
Nasa has redesigned the tank to try to minimise foam loss but admits some breakaway is inevitable whenever a shuttle makes the eight-and-a-half-minute ascent to orbit.
Engineers will continue to scrutinise detailed photos of the latest lift-off to check on the structural integrity of Discovery.
And when the vehicle nears the space station on Thursday, it will perform a backflip so that the ISS crew can inspect further the shuttle's heat-resistant surfaces, particularly on its belly.
The mission has been designated STS-121. Apart from Lindsey and Reiter, the crew comprises pilot Mark Kelly and mission specialists Michael Fossum, Lisa Nowak, Stephanie Wilson, Piers Sellers.
Sellers, who was born in the UK, will lead two or three spacewalks, depending on the length of the mission.
At least one of the walks will be devoted to testing materials and repair techniques that could be used to fix the shuttle's surface tiles in the event of launch damage.
Sellers and Fossum also plan to test the shuttle's 15m-long (50ft) robot arm coupled with a new inspection boom, to see if they are steady enough to serve as a work platform in case astronauts have to make repairs on the ship's underside.
The current mission plan has Discovery coming back to the Kennedy Space Center on 16 July.