Sun-powered plane Solar Impulse 2 left Seville in southern Spain on Monday for the penultimate leg of its record-breaking round-the-world journey.
The zero-fuel aircraft took off from Seville at 0420 GMT en route for Cairo, Egypt on a trip that is expected to take 50 hours and 30 minutes, Reuters reports.
The plane has more than 17,000 solar cells built on its wings and cruises at a speed of about 70 kilometers per hour (43 mph) at a speed comparable to a car.
Mission managers aim to land in Cairo in the morning when the weather is most favorable.
"The winds for landing are good from about 2AM until 8AM," Raymond Clerc, flight director, told BBC.com.
"Then, if we were to land afterwards, the temperatures on the ground would be too high, and it would be a problem for the structure [as we move Solar Impulse to the hanger]. If we're flying, it's not a problem because we're ventilated by the air speed," he added.
According to mission managers, they have to be particularly careful not to expose the plane's solar cells to too much heat when it is stationary on the ground.
Two pilots shared flying duties for the solar-powered plane's trip around the world and are now about to take one more turn at the aircraft controls.
Pilot Andre Borschberg will be in charge for the Seville-Cairo route, while Bertrand Piccard will complete the journey taking Solar Impulse 2 back to Abu Dhabi, where the record-breaking journey began in 2015.
Borschberg said he felt emotional knowing that they are about to make the final journey in the plane.
"It's meaningful obviously because it's my last flight in this round-the-world epic. I've started to think about it," Borschberg told BBC.com.
"I'm happy that we get close to the end but also prudent knowing that it is not done yet. I have to stay really focused."
After this leg, Solar Impulse 2 will be flying to Abu Dhabi, which was where the journey began in 2015.
The penultimate flight will take the plane over the Mediterranean Sea, crossing through the airspace of five other countries, including Tunisia, Algeria, Malta, Italy and Greece, before ending in Egypt where the plane is supposed to land in the Egyptian capital.