A truck driver is missing after a semi-trailer went over a cliff and burst into flames near Kangaroo Valley in the NSW Southern Highlands.

Police said the truck went over the cliff on Moss Vale Road and burst into flames about 2:00am.

The fire was extinguished but excessive heat from the wreckage prevented rescuers from searching the cabin for the missing driver.

Shoalhaven Rural Fire Service Deputy Andrew Fielding was among the first on the scene.

He said the site was very difficult to get to.

"When we arrived the truck was over the side, upside down and well alight," he said.

Police rescue officers search the wreckage of the truck. ( ABC News: Billy Cooper )

"Crews took approximately 30 to 35 minutes to extinguish the fire and to render it safe so the ambulance rescue could investigate further.

"The incident was very difficult to get to, about a 40 degree angle. We had to use the hoses to drag ourselves up and down."

It is unclear what the truck was carrying but the cargo is believed to be non-toxic and not explosive.

The accident happened just north of Bunkerhill Road at Barrengarry Mountain.

Deputy Fielding said it was a very steep section at the bottom of Moss Vale Road on the second hair pin.

"I believe this might be the third or fourth accident in a number of years," he said.

A charter bus went over the edge of the road at the same location in 2010, killing the driver and injuring 28 passengers.

Moss Vale Road is now open but alternating traffic conditions are in place and delays are expected.

The clean-up and salvage operation is expected to take most of the day.