Shona Robison conceded her role as health secretary in the Scottish Government had been "at times very challenging" as she quit Nicola Sturgeon's cabinet.
She had taken on the role in 2016 when Ms Sturgeon, her close friend, became the First Minister.
A failure to meet key NHS waiting times resulted in opposition politicians in the Scottish Parliament heaping pressure on her.
She had also faced calls to quit after financial problems in NHS Tayside - which includes her Dundee East constituency.
Health board chiefs there used £3.6 million from its endowment fund, which is made up of donations from the public or bequests in wills, to help it break even in 2013-14.
In her resignation letter Ms Robison (pictured), a former public health minister, said she had reached a point in life where she "would be best to step down from a role in government".
Ms Robison, who split from her husband, former SNP depute leader Stewart Hosie in 2016, stated: "This last year has been particularly challenging for me personally, losing both my parents, having a health scare of my own and some big changes in my personal life."
She thanked Ms Sturgeon for her "support during these difficult times", and added: "I have entered a new chapter of my life, including a new relationship, where it would be good to take time to focus on those closest to me, who have too often had to come second place to my job, which has been hard for us all."
The First Minister said while Ms Robison was no longer part of the cabinet, she would continue to seek her counsel "as a colleague and a friend".
Ms Sturgeon thanked her for her "hard work in government" and added: "Our friendship has always been extremely important to me."
Ms Robison is succeeded as health secretary by Jeane Freeman - a former student member of the Communist Party who went on to become an adviser to former Labour first minister Jack McConnell.
She is promoted from the post of social security minister, working on the introduction of a new devolved benefit system for Scotland.
But Labour said her appointment to the high-profile role of health secretary was "surprising" claiming Ms Freeman was responsible for smearing a nurse who challenged the First Minister during a 2016 TV election debate.
Claire Austin was attacked after telling the SNP leader her wage as a nurse had left her struggling to pay bills, saying she had resorted to using foodbanks.
A Labour spokesman said: "It is surprising that Nicola Sturgeon has appointed the person behind smearing a nurse who had the guts to challenge the First Minister during the election television debate.
"There are huge challenges in the health portfolio, especially in terms of funding and staffing. We need a health secretary that is going to support staff and stand-up for patients."
Peter Bennie, chair of the British Medical Association in Scotland, said the introduction of minimum unit pricing for alcohol during Ms Robison's period as health secretary had been a "key success" for the Government
Mr Bennie said: "I congratulate Jeane Freeman on being appointed Health Secretary. At the BMA, we look forward to working constructively with her, as we did with Shona Robison."
He added: "This is a challenging time for the NHS in Scotland and we need to see more substantive efforts to tackle the growing gap between resources and demand for services.
"We also need to see concerted efforts to tackle recruitment and retention and this must include a significant pay increase to start addressing the unacceptable pay restrictions that doctors have faced in Scotland for several years."
Copyright (c) Press Association Ltd. 2018, All Rights Reserved. Picture (c) Andrew Milligan / PA Wire.