Health Secretary Alan Milburn has quit the cabinet in a move that took Westminster completely by surprise.
Milburn: Politics is a crazy world
Mr Milburn told the BBC he had decided to leave the government because the demands of the job conflicted with having a young family in the north east.
Speculation had been rife that there would be changes in the cabinet but no-one predicted such a key moderniser would leave the government.
Despite fighting a series of tough political battles in recent months, particularly over foundation hospitals, Mr Milburn said his career had to take second place to his two young sons and his partner Ruth.
He told the BBC that like many families they had tried to juggle commitments but in the end something had to give and in this case it was the "crazy" life of politics.
"The only difference between me and families up and down the land who have to deal with this on a continual basis, is that I have got to do it on TV," he said.
"[Politics] is a completely crazy way to run your life - and I have to get a life."
The resignation was announced after the prime minister returned from Paris where he had dinner on Wednesday night with French president Jacques Chirac.
In his letter Mr Milburn wrote: "It is not a political decision for I support you totally in what you are trying to do - it is entirely personal."
The prime minister's letter thanked Mr Milburn for his contribution to the government and the NHS in particular.
Senior Lib Dem Menzies Campbell said that Mr Milburn's departure weakened the prime minister.
That view was echoed by senior Labour backbencher Ian Gibson who said: "He's lost Mandelson, he's lost Stevie Byers, Estelle Morris was a star too and now Milburn. The team is falling apart, it seems."
The chief executive of Macmillan Cancer Relief, Peter Cardy, said Mr Milburn had paid a "pivotal role" in developing and introducing the NHS cancer plan.
Unison general secretary Dave Prentis - who represents many NHS workers - praised Mr Milburn's dedication.
"Although we had some disagreements on the way forward I believe Alan took
very seriously the difficult job he had to do in turning around our NHS after 20
years of neglect," said Mr Prentis.