The shuttle Discovery began its 2,232-mile (3,591-km) journey home to Florida's Kennedy Space Center from Edwards Air Force Base early Friday California time.
It is being carried on top of a modified Boeing-747 jumbo jet and will make two stops - in Oklahoma and Louisiana - before arriving in Florida on Saturday.
The US space agency, Nasa, says the transportation of the orbiter across the country will cost about $1m.
Bad weather forced the shuttle to touch down in the desert on 9 August instead of its main landing site in Florida.
During the 14-day mission in space, astronauts had to make unique repairs amid fears that Discovery could disintegrate during the re-entry like its sister ship Columbia in 2003.
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