Ruth Kelly is to step down transport secretary to devote more time to her family.
"It was a decision taken absolutely completely for family reasons,'' the mother of four said.
"I have relied on the support of family and friends and now I think it is time to step back and repay them.''
Prime Minister Gordon Brown denied he had any differences with Ms Kelly, who refused to back the government over the Human Fertilization and Embryology Bill.
"There are no political issues between Ruth and me,'' Brown told the BBC's Today radio programme this morning. "It is about her family and her personal life for her future.''
Ms Kelly, a Roman Catholic, stressed her faith is private and not relevant to her job.
She took office in 2007 and has served as the member of Parliament for Bolton West since the May 1, 1997, general election that swept the Labour Party to power after 18 years in opposition.
Ms Kelly leaves her successor decisions on whether London's Heathrow airport should be expanded to include a third runway and a sixth terminal. She had been due to give the government's decision this autumn.
They will also need to steer rail expansion plans and address the concerns of motorists and hauliers over higher fuel prices and proposed charges for road use.
The government also faces public grievances over rail fares that are rising faster than the rate of inflation. (Source: Bloomberg).