Amanda Pritchard, the first female chief executive of the NHS in England, is stepping down from the role.
In a statement Ms Pritchard said it had been a "hugely difficult decision for me to stand down".
"It has been an enormous privilege to lead the NHS in England through what has undoubtedly been the most difficult period in its history."
She took up the post in 2021 and played a central role in the official response to the Covid pandemic.
Before that, she was NHS England's chief operating officer, head of Guy's and St Thomas' NHS Trust in London and an adviser in Tony Blair's government.
Her departure comes less than a month after two influential House of Commons committees discussed her suitability to lead the NHS through a period of what Prime Minister Keir Starmer has said will be the biggest overhaul of the service.
As to the timing of her resignation, some words in her letter are significant.
She noted that there is due to be radical reform of the size and functions of NHS England and the Department of Health and Social Care to "drive the government's reform priorities" and that the "step change required" would be best served by new leadership.
Sources have indicated that the government wants to bind NHS England closer to the Department of Health to push ahead with changes, including shifting the focus from hospitals to community care.
Health Secretary Wes Streeting may well have felt the need to find a new leader, and Amanda Pritchard possibly felt that after several years at NHS England she did not want to be on a tighter rein.
Amanda Pritchard joined NHS England in 2019 as number two to the then chief executive Sir Simon, now Lord Stevens. Senior health sources have indicated that the organisation had a degree of autonomy at the time, and the top job she then took on in 2021 was different to what was now envisaged by the Labour Government.
"Wes Streeting is entitled to shape things as he wishes", said one, "but the role of NHS England chief executive will change".
The reality is that whoever is appointed, the government faces huge challenges cutting waiting lists for operations and treatments, and reducing long waits in emergency departments.