Low clouds threatened to delay the launch for the second day in a row. But then conditions improved, and Endeavour roared off the launch pad, lighting up the sky.
"Looks like the weather came together tonight," launch director Mike Leinbach told the astronauts right before liftoff. "It's time to go fly."
It was a spectacular show for crowds who came out to watch what was expected to be the last time that a space shuttle took off in darkness.
NASA's aging shuttle fleet is headed toward retirement, with just four more missions scheduled.
Endeavour will spend a couple of days traveling to the International Space Station. The six-person crew is carrying the Tranquility module, a final addition to the space station. This room will be equipped with a set of observation windows that will give astronauts unprecedented views and help orchestrate outside work, like spacewalks.
Three spacewalks are planned during the 13-day mission to install Tranquility.
The 23-foot-long section contains a special observation room called a cupola, which allows for a 360-degree view of operations outside the space station.
Tranquility will also house the Colbert Treadmill, named for comedian Stephen Colbert.
Information in this report comes from NPR's Nell Greenfieldboyce, Mark Simpson of WMFE in Orlando and The Associated Press.