David Cameron lost one of his most experienced Cabinet members, as Lord Strathclyde resigned as Leader of the House of Lords.
The 52-year-old peer told Mr Cameron in a letter that he wanted to return to his career in the private sector and "take up other threads of my life and other interests".
He has been replaced as Leader of the Lords by Lord Hill of Oareford, who also becomes Chancellor of the Duchy of Lancaster and a member of the Privy Council.
Lord Strathclyde entered the House of Lords as a hereditary peer in 1986 and was first appointed to Government by Margaret Thatcher in 1988 as a trade and industry spokesman.
He has remained on the Conservative front benches for 25 years, serving as a whip and a minister in the departments for employment, environment, Scotland and trade and industry in the Thatcher and Major administrations.
He was one of the hereditary peers elected to remain in the reformed upper chamber in 1999 and served as opposition leader in the Lords from 1998 until the creation of the coalition Government in 2010, when he was appointed Leader of the Lords.
In his letter, he said that, when first appointed to Government in 1988 he "never believed it was a career for life".
Lord Strathclyde told the PM: "I started my working life in the private sector and at some stage always hoped to return. I would like to do so now. While I have the highest respect for the privilege and duty of public service, I do not see a political career as the cap to everything and would like, while there is still time, to take up other threads of my life and other interests".
Lord Strathclyde said he had always hoped to provide a "smooth handover to a strong successor" and with the prospect of Lords reform now "effectively over" and the Government "beginning to bring recovery and change for the better", he felt that the upper House now needs "a new Leader to see it through different challenges in the years ahead".
In a letter accepting his resignation, Mr Cameron praised Lord Strathclyde as "an outstanding Leader of the Lords", adding: "I entirely understand your desire to pursue other interests." Mr Cameron made clear that a return to the front line of politics was not ruled out, telling the peer: "I do hope that at some point in future years you will have a further contribution to offer."