Larry Hogan, a popular former Republican governor of Maryland, has announced a run for the US Senate.
A prominent critic of Donald Trump, Mr Hogan stepped down from leading a third-party movement called No Labels last month.
He announced he was running in his home state in a video posted on X on Friday.
Mr Hogan said he was entering the race "not to serve one party - but to stand up to both parties, fight for Maryland, and fix our nation's broken politics".
"It's what I did as Maryland's governor, and it's exactly how I'll serve Maryland in the Senate," he said.
The seat is currently held by Democratic Senator Ben Cardin, who has announced his retirement. Mr Hogan is so far the only well-known Republican to enter the race.
Democratic Rep. David Trone and Prince George County executive Angela Alsobrooks are competing in the Democratic primary for the seat.
Before leaving office with high approval ratings, Mr Hogan won two terms to serve as governor of Maryland - which has long shown preference for Democrats.
He was the first Republican governor in 64 years to win a second term, casting himself as a moderate at a time when the party lurched to the right.
Two years ago, Republicans had asked him to challenge Senator Chris Van Hollen, a Democrat, but he turned down the suggestion.
Mr Hogan had been serving as co-chair of the third-party group, No Labels, which sparked speculation that he might run for president as a third-party candidate.
He endorsed Nikki Haley, however, who has fallen far behind Mr Trump in the race for the Republican presidential nominee.
Republicans need to flip two seats to take control of the Senate if President Joe Biden wins his re-election campaign, but only one if their party retakes the White House.
Another state where Republicans are gearing up to unseat a Democrat is Montana, where state representative Matt Rosendale also announced a Senate bid on Friday.
His announcement kickstarts a bitter primary battle in the Republican party in the critical race to defeat current Democratic Senator Jon Tester.
The conservative hardliner will go up against former Navy SEAL Tim Sheehy, who has been endorsed by the National Republican Senatorial Committee and also former President Donald Trump.