The single-person, solar-powered Solar Impulse aircraft departed St. Louis, Missouri early Friday en route to Cincinnati and then the US capital, organizers said.
The plane, which runs on four electric propellers powered by 12,000 solar cells mounted on the plane's 63 meter wingspan, lifted off in the dark from Lambert-St. Louis International Airport at 0902 GMT.
At the controls was Swiss pilot Andre Borschberg, who is taking turns with compatriot Bertrand Piccard on different legs of the flight across the United States.
The Solar Impulse takeoff was broadcast live on the organizer's website, live.solarimpulse.com.
The Solar Impulse can fly at night by reaching a high elevation of 27,000 feet (8,230 meters) and then gently gliding downward, using almost no power until the sun comes up to begin recharging the solar cells.
However Borschberg will be flying lower than usual Friday "because the winds are much too strong at high altitudes," said flight director Raymond Clerc just ahead of the flight.
The flight is expected to last 17 hours, and the giant plane is expected to arrive at the Cincinnati Municipal Lunken Aiport in Ohio at 9 pm (0100 GMT).
Strong cross winds and heavy air traffic are expected to make flying challenging.
The difficult weather thwarted plans for a direct flight from St. Louis to Washington DC.
The Solar Impulse usually lands around 2 am, when traffic at the airports has subsided, but since there is less traffic at the Cincinnati municipal airport, organizers said they were allowed to land earlier than usual.
On Saturday Piccard will take the controls and fly the plane out around 1200 GMT en route to the US capital, landing sometime after midnight at the Washington Dulles International Airport, organizers said.
The Solar Impulse project, founded and led by Piccard and Borschberg, aims to showcase what can be accomplished without fossil fuels, and has set as its "ultimate goal" an around-the-world flight in 2015.
The first leg of Solar Impulse's US tour took place on May 3, when Piccard flew the aircraft from the San Francisco, California area to Phoenix, Arizona.
St. Louis was chosen as the Midwest stopover to pay homage to aviation pioneer Charles Lindbergh and his "Spirit of St. Louis," the first plane to fly from New York to Paris non-stop.
Explore further: Material generates steam under solar illumination