Malaysia Airlines says flight MH370 carrying 239 people bound for Beijing "has lost contact" with air traffic control.
The state-owned carrier said the Boeing 777-200 disappeared this morning at 2.40am local time.
It left Kuala Lumpur just after midnight and was due to arrive in Beijing at 6.30am local time.
Malaysia Airlines said the flight was carrying 227 passengers (including two children) and 12 crew members, from 13 different countries.
They include 153 Chinese nationals, 38 Malaysians, 12 Indonesians, seven Australians, four Americans, two New Zealanders, two Ukrainians, two Canadians, one Russian, one Austrian, one Italian, one Taiwanese and one Dutch citizen.
The carrier said it was working with the authorities who have activated their search and rescue teams to locate the aircraft.
It is also contacting the next-of-kin of the passengers and crew.
"Our thoughts and prayers are with all affected passengers and crew and their family members," Malaysia Airlines CEO Ahmad Jauhari Yahya said in a statement.
The airline said it would provide "regular updates" on the situation and has set up the phone line +603 7884 1234 for concerned members of the public.
China's state news agency reported that the plane lost communication over Vietnam with air traffic control in the Ho Chi Minh area and that radar contact also was lost.
Citing a local Vietnamese media report, the agency said a Vietnamese search and rescue official reported that signals have been detected from the plane from about 120 miles (220km) southwest of Vietnam's southernmost coastal province of Ca Mau.
It said there had not been any reports received yet about any aircraft that has crashed.
Chinese Foreign Minister Wang Yi said in a statement: "This news has made us all very worried.
"We hope every one of the passengers is safe. We are doing all we can to get more details."
Malaysia Airlines has 15 Boeing 777-200 jets in its fleet of about 100 planes.
If the plane is found to have crashed, the loss would mark the second fatal accident involving a Boeing 777 in less than a year, after an unblemished safety record since the jet entered service in 1995.
Last summer, an Asiana Airlines Boeing 777 crash landed in San Francisco, killing three passengers.
Boeing said it was aware of reports that the Malaysia Airlines plane has gone missing and was monitoring the situation, but had no further comment.