Saints have begun the hunt for a new manager after reluctantly allowing George Burley to take charge of Scotland.
It was too good an opportunity to turn down for the 51-year-old who leaves St Mary's after 25 months at the helm.
Burley said: "I am very sad to be leaving Southampton. It will be a big wrench because it is a fantastic club with top facilities, some terrific people, a great bunch of players and magnificent supporters.
"I have had full backing from the board and I have thoroughly enjoyed my time here.
"I'd like to thank all the staff there for their help and support while I have been at St Mary's. I am sure they will soon get back to the Premiership where they belong and I really wish them all well.
"However this was a once-in-a-lifetime opportunity which I could not turn down.
"It was a huge honour even to be considered for the post and I am thrilled to have been offered it.
"To take charge of your country is perhaps the highest accolade you can get as a manager and I am really looking forward to that challenge."
Burley took over from Harry Redknapp in December 2005 and immediately set about rebuilding the squad. He got a quick and harsh lesson about the size of his task as Saints crashed 3-0 at Watford in his first game on Boxing Day.
He said at the time there were players who did not want to be there and some who were not what he was looking for.
A major clear-out followed with Antti Niemi, Nigel Quashie and club record signing Rory Delap all seeking their fortunes elsewhere.
And Burley was effectively forced to sell hot prospect Theo Walcott who, as a 16-year-old, would have been able to move for nothing if Saints had not negotiated a £12m move.
It was very much a time of transition for Saints who lost their first three league games under the new boss and then flirted briefly with the relegation zone before finishing strongly to end the campaign in 12th place.
The summer change of regime saw the club splash out £7m on players in a bid to seal a return to the Premiership in the last year of their parachute payment.
They played some exciting football as they finished the campaign strongly with a remarkable 6-0 win at Wolves proving the launchpad for a promotion push.
And they went agonisingly close with only the heart-break of a penalty shoot-out standing between them and a place in the Play-off final at Wembley.
The loss of the parachute payment had a huge effect on Saints who were forced to sell during the summer.
Key departures included two more hot prospects in Gareth Bale and Kenwyne Jones as well as Chris Baird, Leon Best and Pele.
That forced Burley to rebuild for a second successive season but this time a lack of funds and a crippling injury list made the task much harder.
He stuck to his principles of playing an attractive passing game but it was tough to get a settled side with some fans growing impatient at a perceived lack of progress.
But despite more boardroom upheavals, Saints hung onto the coat-tails of the play-off race and are still in a decent position for the new man to launch a promotion push.
They now need to find a strong replacement for Burley who has been freed to take a once-in-a-lifetime chance to take charge of his country's bid for the 2010 World Cup.
His 109 games as Saints manager brought 45 wins, 25 draws and 39 defeats.
His last game in charge was a 1-1 draw at Plymouth and he now embarks on a new challenge with the club's thanks for his hard work.
SourceBurley's gone

He was a decent manager, had his ups and downs with the club....I wish him well coachin Scotland