US Defence Secretary James Mattis is resigning, the latest in a string of senior US officials to do so.
His announcement came a day after President Trump said he was withdrawing troops from Syria – a decision General Mattis is understood to oppose.
In his resignation letter, Gen Mattis strongly hinted at policy differences with Mr Trump.
He said the president had the right to appoint someone “whose views are better aligned with yours”.
Gen Mattis, 68, will leave the job in February. President Trump has not immediately named a successor, but said one would be appointed shortly.
Members of Congress from both sides of the political divide have reacted with shock to the resignation.
Senate Majority Leader Mitch McConnell, from Mr Trump’s own Republican Party, said he was “distressed” to hear the resignation was reportedly due to “sharp differences” that Gen Mattis had with the president.
Gen Mattis alluded to disagreements with the president in a number of policy areas.
In his letter, addressed to Mr Trump directly, he described his views on “treating allies with respect” and using “all the tools of American power to provide for the common defence”.
“Because you have the right to have a Secretary of Defense whose views are better aligned with yours on these and other subjects, I believe it is right for me to step down from my position,” he wrote.