Air Wales has announced it is to stop running scheduled passenger flights from next month.
Air Wales will cease flights on 23 April
Up to 80 jobs will be lost as the Cardiff International Airport-based company moves to charter flights and freight transport only.
It blamed the move on "spiralling costs" and "aggressive competition" from larger low-cost airlines.
Three airlines are expected to take over routes to destinations including Aberdeen, Cork and Manchester.
The news came as ferry operator Stena Line announced it was cutting sailings between Holyhead and Ireland, also blaming budget airlines and rising fuel costs.
In a statement, Air Wales said it was becoming "increasingly impossible for independent regional airlines such as Air Wales to operate profitably without substantial subsidy".
Air Wales currently flies to 10 destinations from Cardiff and a number of others from bases in France, Manchester and Ireland.
The company is holding discussions with other carriers over handing on its routes to them.
Three have been announced already, with Aer Arann flying Cardiff to Cork, Eastern Airlines taking over Brussels, Aberdeen and Newcastle services and Air Southwest flying to Manchester and Newquay.
Just last month, it re-launched the service linking Cardiff with Brussels, with Welsh assembly government support.
An assembly government source said the money was awarded to the airport rather than the airline, so it had not been lost but would need to be taken over by another airline.
It is also hoped that staff losing their jobs will be offered posts with the companies taking over the routes.
Air Wales chairman Roy Thomas said they had made the decision "with sadness and regret".
"Increased costs and high competition in the market place have made it virtually impossible to exist as a passenger focused airline," he said.
"Without the vast economies of scale required to sustain and successfully compete in the passenger airline business today, it has become clear that Air Wales now needs to centre on charter and freight services to continue operating in the airline industry."
WHERE FLIGHTS ARE SWITCHING
Aer Arann - six flights a week, Cardiff to Cork, from 24 April
Air Southwest - twice-daily Cardiff to Manchester, Cardiff to Newquay, from 10 April
Eastern Airlines - Cardiff to Aberdeen, Cardiff to Brussels, Cardiff to Newcastle, from 24 April
Source: Cardiff International Airport
He added all passengers booked with the airline after 23 April would get a full refund and help finding alternative flights.
Assembly Economic Development Minister Andrew Davies said he was "disappointed" to hear the decision but delighted three airlines had come forward to take over some routes.
The airline began operating in November 1999, flying from Cardiff International Airport and Pembrey in west Wales to London, before expanding to Cork and other routes.
Cardiff International Airport's managing director Jon Horne said: "We are sad to learn that Air Wales is to cease scheduled operations and hope that the impact on jobs can be minimised.
"Meanwhile, other airlines are preparing to announce scheduled operations from Cardiff International on routes that Air Wales will be giving up."
The announcement of the end of scheduled services came hours after Stena Line ferries announced it was cutting back fast ferry services between Holyhead and Dun Laoghaire, near Dublin.
Dr Anthony Beresford, a lecturer in transport in the Cardiff Business School said the ferry companies faced long winters and "peaky" sailing times.
He said: "Fuel costs are high yes, but they would be better off running smaller ships. The problem they've got is that they have very large vessels which are very thirsty to run.
"The impact of this is that if you cut the frequency, it is directly going to tend to push jobs into the part-time and informal sector".
Dr Beresford said the rising cost of fuel being blamed for the airline cuts was "quite frankly a red herring because other airlines are experiencing the same problem".
He added: "Yes, there is competition from other airlines, but the main competition budget airlines face [within the UK] is from people driving to their destination."