Atlantis fired jets around 4:20 a.m. EDT to leave the International Space Station behind for the last time and begin a shuttle's final trip home.
The second of two separation burns came as Atlantis flew about 680 feet below the outpost after completing what NASA TV called a "textbook" final flyaround over the top.
"Get her home safely, and enjoy the last couple of days of space shuttle Atlantis," astronaut Dan Tani, in Houston's Mission Control Center, radioed in a congratulatory message as the "Orbit 1" team of flight controllers ended their last shift of the mission.
"It's been an incredible ride," replied Atlantis commander Chris Ferguson. "We're glad to be headed home."
During the flyaround, station cameras showed the last exterior views of Atlantis before its planned landing at Kennedy Space Center at 5:56 a.m. Thursday.
The orbiter looped above and behind the station, at one point flying partially behind one of the station's eight golden solar arrays.
Finally Atlantis faded into darkness during an orbital sunset, and the two orbiting crews exchanged final thanks and goodbyes.
"Atlantis now on its way, beginning the final leg of its journey to the Kennedy Space Center," said Rob Navias, a NASA TV commentator.
At 6:19 a.m., the four Atlantis atronauts are scheduled to begin a final heat shield inspection to confirm its fitness for Thursday morning's atmospheric re-entry.