US Secretary of State Colin Powell has resigned but says he will stay in his post until a successor is found.
Powell said it had been a great honour to serve his country
The 67-year-old said it was always his intention to serve one term, and it was time to return to a private life.
President Bush praised Mr Powell as both a soldier and a diplomat whose presence would be missed.
Mr Powell's resignation was announced along with three other cabinet members, bringing to six the number of key figures to leave the 15-member cabinet.
National security adviser Condoleezza Rice and UN ambassador John Danforth are tipped as possible successors.
"It has been my great honour and privilege to serve my nation," said Mr Powell, announcing his resignation at a State Department briefing.
"I will always treasure the four years I spent working with President Bush and the wonderful men and women of the department. I think we accomplished a great deal."
He said he and President Bush had discussed his eventual departure for some weeks, and they mutually decided it was the right time for him to go.
Energy Secretary Spencer Abraham, Agriculture Secretary Ann Veneman, and Education Secretary Rod Paige also announced their intention to step down.
White House spokesman Scott McClellan said all had agreed to stay in their posts until successors could be found and approved by the Senate.
Mr Powell said he expected to remain in his post for several weeks, and would still go ahead with a visit to Chile on Wednesday, the Middle East next week, and to Europe in December.
THE POWELL YEARS
First African-American to serve as secretary of state
First US official to use the word 'war' after 9/11
Persuaded President Bush to involve UN on Iraq issue
Key speech to UN on Iraq's WMD ahead of Iraq war, later discredited
Several ill-fated peace missions to Israel and the Palestinians
Powell was the last senior US politician to visit Yasser Arafat
Underwent successful operation for prostate cancer
Accused Sudanese government of complicity in "genocide" in Darfur
In a statement President Bush praised Mr Powell for his diplomatic skills as a key architect of the Broader Middle East initiative, and for diffusing tensions with India and China.
Colin Powell, he said, was valued both as a public asset and a private friend.
"Colin Powell is one of the great public servants of our time," he said in a statement.
"He is a soldier, a diplomat, a civic leader, a statesman, and a great patriot."
State Department officials said Mr Powell submitted his resignation to President George W Bush on Friday, and informed his staff on Monday morning.
The 67-year-old reportedly promised his wife he would serve only one term as secretary of state. He said in his resignation letter it was time to return to a private life.
During his press conference, Mr Powell outlined the key foreign policy challenges still facing the US.
He said the country must continue what he called the global war on terror, consolidate gains in Afghanistan, defeat the ongoing insurgency in Iraq and take advantage of a new opportunity in the Middle East peace process after the death of Palestinian leader Yasser Arafat.
He also spoke of working closely with allies in Asia to resolve the North Korea nuclear issue, and with Europe and the International Atomic Energy Agency on Iran's nuclear programme.
John Ashcroft, Attorney General
Don Evans, Commerce
Colin Powell, Secretary of State
Spencer Abraham, Energy
Ann Veneman, Agriculture
Rod Paige, Education
The BBC's Jill McGivering at the State Department said Mr Powell's resignation had been expected.
He was widely seen as a moderate in a cabinet of hawks, whose views on Iraq put him at odds with the White House.
Correspondents say he proved a popular and successful American envoy, often seen by the international community as a moderating force.
One of his most high-profile moments was his appearance before the UN Security Council on 5 February 2003, to argue that Saddam Hussein must be removed because of Iraq's possession of weapons of mass destruction.
He later admitted that some of the information in that speech - particularly about mobile laboratories allegedly used for making biological weapons - "appeared not to be ... that solid."