The Philadelphia Inquirer first reported the news of Toomey's decision not to run for reelection or for governor in 2022.

Toomey first won his seat in a tight race in 2010, before winning a narrow reelection in 2016 in one of the most expensive Senate races in history, which helped Republicans hold onto their Senate majority as President Donald Trump took office.

Now, Toomey's retirement means that both a Senate seat and the governorship will be open in Pennsylvania in 2022, setting off a scramble in both parties for candidates.

Democratic Lt. Gov, John Fetterman, who ran for Senate in 2016 and lost in the primary, didn't rule out running for the seat. Asked if he would enter the race, he said in a text message "2022 is wide open." State Treasurer Joe Torsella will seriously consider running, according to a person familiar with his thinking.

Attorney General Josh Shapiro is considered a likely contender for higher office in 2022, while a Democratic official mentioned Val Arkoosh, chair of the Montgomery County Board of Commissioners in the Philadelphia suburbs, as a possible Senate candidate. And several members of the congressional delegation are likely to be in the mix as well, with Reps. Conor Lamb and Chrissy Houlahan among those considered potential candidates for statewide office.

On the Republican side, former Rep. Ryan Costello will look seriously at running, according to a person familiar with his thinking. Rep. Mike Kelly is also considered a potential candidate. Jeff Bartos, a real estate developer and former candidate for lieutenant governor, said in a statement he would be having conversations with family in the coming weeks and would have more to say about a potential run after the election.

Former Rep. Charlie Dent, a moderate Republican and vocal Trump critic, is taking a look at the opening, according to a person familiar with his thinking. Former GOP Rep. Lou Barletta, who lost the 2018 race for Senate, said he would make a decision after the election.

State Sen. Mike Regan, state Rep. Martina White and Chester County Commissioner Michelle Kichline could also be potential candidates, according to one GOP operative.

During his 16 years in Congress so far — six in the House, 10 in the Senate — Toomey has forged a reputation as a low-key conservative who focuses more on tax and spending issues rather than social conservative hot-button topics. He currently serves on the Finance, Budget and Banking committees. A Harvard graduate, Toomey served a key role on the 2011 “supercommittee” that tried to forge a bipartisan long-term spending panel, although the panel failed to reach consensus.

Toomey is a loyal vote for McConnell and Trump on most issues, although it’s clear that some of Trump’s behavior while in office has upset the cautious Pennsylvania Republican, who waited until Election Day in 2016 to announce that he was voting for his party's presidential nominee.

For instance, Toomey criticized Trump’s decision to commute Republican operative Roger Stone’s criminal conviction, calling it “a mistake.” Trump responded by branding Toomey “a RINO,” meaning “Republican in Name Only.” Toomey opposed Trump’s decision to declare a “national emergency” at the U.S.-Mexico border in order divert funds to a border wall. Toomey also said Trump was wrong to raise former Vice President Joe Biden during a 2019 call with Ukrainian leaders, though he voted to acquit Trump on impeachment charges related to that episode. And Toomey opposed some of the spending deals agreed to by the Trump administration, arguing they increase the deficit.

Yet Toomey supported Trump’s 2017 tax-cut package, despite the fact that it increased U.S. debt by trillions of dollars. And he’s backed Trump’s judicial nominees, including Supreme Court Justice Brett Kavanaugh.

Charlie Gerow, a Pennsylvania-based GOP strategist, said Toomey's retirement decision "puts in motion a large number of variables."

"There will be a number of candidacies announced both shortly and further down the road," Gerow said. "I think you’re going to have half the legislature and people from the business world and people from academia and maybe even the media announcing their candidacies.”

Burgess Everett, Andrew Desiderio, Jake Sherman and Alex Thompson contributed to this article.