Mitch McConnell, the powerful politician from Kentucky, announced that he plans to step down as the Senate's longest-serving Republican leader in November.
He has served as leader for nearly 20 years, but said it was "time to move on" in a speech on Wednesday.
Mr McConnell has proven key to passing conservative priorities and electing Republicans to Capitol Hill.
He fell out of favour with Donald Trump's wing in recent years, however.
In his speech, Mr McConnell reflected on his long career, his age - 82 - and his family.
He dedicated a large portion of his speech, however, to the importance of US global leadership despite the ideological shift his party has undergone under former President Donald Trump's isolationist rhetoric.
"I know the politics within my party at this particular moment in time. I have many faults, but misunderstanding politics is not one," he said.
"That said, I believe more strongly than ever that America's global leadership is essential to preserving the shining city on a hill that Ronald Reagan discussed," he added.
