The head of the civil service, Sir Jeremy Heywood, has announced his retirement in order to concentrate on his recovery from cancer.
Prime Minister Theresa May has appointed acting Cabinet Secretary Sir Mark Sedwill, who has been standing in for Sir Jeremy since he took leave of absence in June to receive treatment, to take over the role on a permanent basis.
Sir Jeremy, 56, has been Cabinet Secretary since 2012 and head of the home civil service since 2014, and previously served as principal private secretary to prime ministers Tony Blair and Gordon Brown, chief of staff to Mr Brown and Downing Street permanent secretary to David Cameron.
His position as one of Whitehall’s most senior mandarins under four successive prime ministers has led him to be regarded as a key behind-the-scenes influence in the shaping of modern Britain.
Sir Jeremy revealed earlier this year he had been diagnosed with cancer in June 2017, but remained in post during a summer of political upheaval triggered by the shock general election result.
In a personal statement, Sir Jeremy said: "Thirty-five years ago, I joined the civil service as an enthusiastic young economist in the Health and Safety Executive, full of ideas and keen to make change happen.
"Today, I still have all that desire to serve my country and to make a positive difference. It is with great sadness therefore that, on medical advice, I must now retire."
ITV News political correspondent Carl Dinnen said on Twitter this is a "Big change at the top of Government."
Mrs May paid tribute, saying: "Jeremy has given exemplary service to the public in his civil service career. He has worked constantly to improve our country’s future and to deliver for the public, serving prime ministers and ministers of all parties with distinction in the finest traditions of the civil service.
"I am personally grateful to him for the support he has given me as Prime Minister.
"He has made an enormous contribution to public life in our country and will be sorely missed."
In recognition of his distinguished service to public life, the Prime Minister has nominated Sir Jeremy for a life peerage.
Sir Mark, 54, who served as Mrs May’s national security adviser before taking on the Cabinet Secretary role on a temporary basis, said: "The whole public service will want to thank Jeremy for his tireless and outstanding service to our nation, and for the values he exemplifies.
"He has had a profound, positive and lasting impact and will be greatly missed."