Senator Jeff Flake has announced that he will not run for re-election in 2018.
In a speech on the Senate floor that appeared to be aimed at President Donald Trump, the Arizona Republican criticised the "flagrant disregard of truth and decency" that he says is undermining American democracy.
Sen Flake said: "There are times we must risk our careers. Now is such a time."
He has been critical of the path that the Republican Party has taken under President Trump.
Sen Flake said the impulse to "threaten and scapegoat" could turn America and the Republican Party into a "fearful, backward looking people".
Sen Flake was trailing in polls against a conservative challenger.