US Edition The group, led by Neil Laughton, will make the 3,600-mile journey by land and air in the Parajet Skycar, effectively a dune buggy with a fan motor and paragliding wing attached.
After taking off from London on Wednesday, the expedition will travel through France, Spain, Morocco, Western Sahara and Mali, and aims to reach Timbuktu on February 20.
The plan is to drive the Skycar where there are roads, and fly over the Straits of Gibraltar, the Atlas Mountains in Morocco and the trackless wastes of the Empty Quarter of the Sahara.
A supporting group of experienced adventurers will follow the Skycar on the ground in all-terrain vehicles and on motorbikes.
The vehicle was designed by engineer Giles Cardozo in just 18 months, and the expedition team say it is the "world's first road legal biofuelled flying car".
The powerful fan propels the car forward and the "ParaWing" can give enough lift to allow the Skycar to take off from any field or airstrip 200m or more in length.
Once airborne, the pilot steers by using cables to alter the wing's shape, and should the engine fail, the Skycar would float gently to the ground, the descent slowed by the wing.
The Skycar can change from ground to flying mode in just three minutes, can reach altitudes of up to 15,000 feet, and has a normal cruising height of 2,000-3,000 feet.
On the ground the car has a range of 240 miles, top speed of 108mph and independent four-wheel suspension means it can cope with the toughest terrain.
Mr Laughton, 45, who lives in West Sussex, said he was particularly looking forward to visiting villages in West Africa.
Speaking yesterday prior to today's departure, he said: "I just can't wait to see their faces when we fly in and start playing football with them.
"I don't think they will be able to believe somebody in a flying car has just visited them."
The team had hoped to fly the Skycar over the English Channel but were prevented by Civil Aviation Authority (CAA) regulations.
Mr Cardozo, from Dorset, said: "It's frustrating but that's the way it goes.
"It's a big project to get an aircraft fully certified."
Mr Laughton, who is a qualified pilot and served in the SAS, said the journey through the Sahara posed particular dangers.
"We have been following the Foreign Office advice on the political situation in the area north-west of Timbuktu.
"There is a significant kidnap threat in that area so we have to be very careful and will be choosing our route very carefully and not publicising it too widely."
Mr Laughton said that, after 20 years of expeditions to remote parts of the world, his family had learned to steel themselves to his adventures.
A spokesman for the CAA said there were no regulations prohibiting the Skycar from flying across the Channel, but as it does not have full European certification, permission would also be needed from the French authorities.
The CAA had worked with the Skycar team to help get a permit to fly, he added.