Foreign Office minister Mark Simmonds has resigned from the government, the second to depart in less than a week.
No 10 said Mr Simmonds made the decision "several weeks ago" and said it was unrelated to the events in Gaza which led to Baroness Warsi quitting.
Mr Simmonds has also said he will step down as MP for Boston and Skegness at the general election next year.
Downing Street has announced that James Duddridge will replace Mr Simmonds as minister for Africa.
The prime minister's spokesman said Mr Simmonds had stayed on in the job after announcing his intention to step down, to chair meetings at the UN on the situation in the Democratic Republic of Congo.
In his resignation letter, dated 4 August, Mr Simmonds told Mr Cameron he would "remain supportive of you, your government and the Conservative Party".
In a separate statement to constituents, he said that "despite the enjoyment and personal fulfilment I have found in this role, the lack of support available to MPs with families outside of London and the sacrifice to my family life, has become intolerable".
"At this stage, I need to focus on providing for my family."
Mark Simmonds at-a-glance
Age: 50
Educated: Worksop College and Trent University
Family: Married with three children
MP: First elected, in Boston and Skegness, in 2001
Minister: Foreign Office minister since October 2012
Of his ministerial role, he said: "I am proud of the work I have been able to carry out during my time at the Foreign and Commonwealth Office, enabling and encouraging greater UK Africa Trade and Investment, where huge opportunities exist; ensuring that UK diplomacy contributes to security in the UK and stability in Africa.
"As well as enhancing the partnership between the UK and the Overseas Territories and nurturing our all-important international energy relationships. I am also grateful to the prime minister for allowing me to chair the UN Security Council as one of my last acts as a minister."
In his reply to the resignation letter, Mr Cameron said Mr Simmonds had been a "good friend" and still had "much more to give".
Baroness Warsi resigned as a Foreign Office minister on 5 August, saying the UK's policy on the crisis in Gaza was "morally indefensible".
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