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The UK's top civil servant, Sir Jeremy Heywood, is stepping down to focus on his recovery from ill health.
Sir Jeremy, cabinet secretary since 2012 and head of the civil service since 2014, was already on a leave of absence while being treated for cancer.
Prime Minister Theresa May said he had "made an enormous contribution" and "will be sorely missed".
Sir Jeremy said that leading the UK's civil servants "has been the greatest privilege of my career".
He also thanked Sir Mark Sedwill - who is to succeed him - "for holding the fort so admirably over the summer months as acting cabinet secretary, and to congratulate him on his well-deserved promotion".
The cabinet secretary and head of the civil service is Mrs May's principal adviser.
Proud of Brexit work
Mrs May said: "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."
Sir Jeremy, who joined the civil service as an economist in the Health and Safety Executive 35 years ago, said he still had the "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," he said.
"Since joining the civil service, I have had the privilege of supporting, at close quarters, four prime ministers, two Conservative and two Labour, and the first coalition government for decades, with its first full-time deputy prime minister.
"Throughout my career, I have seen it as my responsibility to look for fresh angles, to challenge lazy thinking and to work with colleagues to find solutions rather than simply identifying problems and obstacles that everyone can admire."
Notable issues Sir Jeremy worked on were the response to the 1990s exchange rate mechanism crisis and the 2008-09 credit crunch and financial crisis.
On Brexit, he said he was "particularly proud of the work Whitehall has done in seeking to bring clarity, shape and practical options to the table for ministers to discuss".
He praised the state of the civil service now, adding: "Despite a number of recent 'noises off' from anonymous commentators, I believe that the service is in robust health, well-equipped to provide the support the country needs over the coming months and years."