Endeavour, which took off from Cape Canaveral, is destined for the International Space Station on a mission that will be one of the last performed by the shuttle programme.
Only four more shuttle flights are scheduled following the pre-dawn blast off at the Kennedy Space Centre in Florida.
Endeavour is carrying a new room for the International Space Station and an observation deck. These are the last major pieces for the orbiting complex.
The shuttle is scheduled to reach the space station on Wednesday, where its crew will spend 13 days. Its flight was delayed a day by cloudy weather.
The Obama Administration has yet to provide specifics on what happens after the last mission this autumn. Nasa's Constellation programme - and its goal of returning to the Moon - has been mothballed by the US government's new budget plan.
Among the crew is the British-born astronaut Dr Nicholas Patrick, originally from Saltburn-by-the-Sea, North Yorkshire. He became a US citizen in 1994.
In 2006 he was part of a seven-member Discovery crew that blasted off for a 12-day mission to the International Space Station.
