Senate Majority Leader Mitch McConnell, R-Ky., speaks to supporters on Oct. 28 in Lawrenceburg, Ky. McConnell retained his seat after acknowledging that tough Senate races could flip control of the chamber to the Democrats.  Associated Press/Timothy D. Easley

WASHINGTON (AP) — Republicans suffered a first setback in the battle for Senate control Tuesday as Democrats picked up a seat in Colorado, but the GOP ousted a Democrat in Alabama. Well-known Republicans held on in South Carolina and Texas.

Republicans sought to retain their Senate majority against a surge of Democrats challenging President Donald Trump’s allies across a vast political map. Both parties saw paths to victory, and the outcome might not be known on election night.

In Colorado, Republican Cory Gardner was among the most endangered senators. His state had shifted leftward in the Trump era, and Democrat John Hickenlooper, a former governor, won the seat.

“It’s time for a different approach,” Hickenlooper said in an live video message posted on Facebook.

White House confidant Lindsey Graham survived the fight of his political life in South Carolina against Democrat Jamie Harrison, whose campaign stunned Washington by drawing more than $100 million in small-scale donations. In Texas, Sen. John Cornyn turned back Democrat MJ Hegar, a former Air Force helicopter pilot, in his hardest-fought election in almost two decades.

Republicans also flipped the seat in Alabama that Democrat Doug Jones had won in a special election as former Auburn football coach Tommy Tuberville was elected in the Trump stronghold.

From New England to the Deep South and the Midwest to the Mountain West, Republicans are defending seats in states once considered long shots for Democrats. The Trump administration’s handling of the COVID-19 crisis, its economic fallout and the nation’s uneasy mood all seemed to be on the ballot.

Trump loomed large over the Senate races as did Democratic presidential nominee Joe Biden. They swooped into key states, including Iowa, Georgia and Michigan, in the final days of the campaigns. Voters ranked the pandemic and the economy as top concerns, according to AP VoteCast, a national survey of the electorate.

Securing the Senate majority will be vital for the winner of the presidency. Senators confirm administration nominees, including the Cabinet, and can propel or stall the White House agenda. With Republicans now controlling the chamber, 53-47, three or four seats will determine party control, depending on who wins the presidency because the vice president can break a tie.

Polls closed in key states where some of the nation’s most well-known senators were on the ballot. In Kentucky, Senate Majority Leader Mitch McConnell fended off Democrat Amy McGrath, a former fighter pilot in a costly campaign, but he acknowledged his GOP colleagues face tougher races.

“We don’t know which party will control the Senate,” McConnell said from Louisville. “But some things are certain already. We know grave challenges will remain before us, challenges that could not care less about our political polarization. We know our next president will need to unite the country, even as we all continue to bring different ideas and commitments to the table.”

In Georgia, two Senate seats were being contested. They could easily be pushed to a Jan. 5 runoff if no candidate reaches the 50% threshold to win.

The Senate will welcome some newcomers as others retire. In Tennessee, Republican Bill Hagerty won the seat held by Sen. Lamar Alexander, who is retiring. Republican Cynthia Lummis, the former congresswoman from Wyoming, won the Senate seat opened by retiring GOP Sen. Mike Enzi.

So far, incumbent senators in less competitive races easily won.

Several Democrats were reelected, including No. 2 leader Dick Durbin of Illinois, Mark Warner in Virginia and Ed Markey, who survived a primary challenge in Massachusetts. Chris Coons kept the Delaware seat once held by Biden, defeating a Republican who previously promoted the baseless QAnon conspiracy theory.

Among Republicans, Tom Cotton in Arkansas, Ben Sasse in Nebraska, Shelley Moore Capito in West Virginia and James Inhofe in Oklahoma won.

Stuck in Washington to confirm Trump’s Supreme Court nominee Amy Coney Barrett a week before Election Day, senators quickly fanned out — some alongside the president — for last-ditch tours, often socially distanced in the pandemic, to shore up votes.

Republican Sen. Thom Tillis joined Trump’s rally in Fayetteville, North Carolina, on Monday. Tillis has struggled against Cunningham, despite the married challenger’s sexting scandal with a public relations strategist. Cunningham traveled around the state Tuesday, talking to voters in Efland, near Durham.

Democrats have more than one route to secure the three or four seats needed to capture the majority, and GOP strategists privately acknowledged that the incumbents will almost certainly suffer defeats in some races.

Arizona could see two Democratic senators for the first time since last century if former astronaut Mark Kelly maintains his advantage over GOP Sen. Martha McSally for the seat once held by the late Republican John McCain.

Even the open seat in Kansas, which hasn’t elected a Democrat to the Senate since 1932, was being contested as the most costly in state history.

In the presidential battleground of Michigan, Republicans have made an aggressive push for John James, a Black Republican businessman, against Democratic Sen. Gary Peters.

In Georgia, GOP Sen. David Perdue, the former business executive Trump calls his favorite senator, tried to stave off Democrat Jon Ossoff, another candidate who has benefited from the “green wave” of campaign donations.

Separately, GOP Sen. Kelly Loeffler faced Republican Rep. Doug Collins, as well as Democrat Raphael Warnock, in a special election for the seat she was appointed to fill after the retirement of GOP Sen. Johnny Isakson.

The Maine race between GOP Sen. Susan Collins and Democrat Sara Gideon was another contest that could push past Election Day if no candidate breaks the 50% threshold. Collins has typically rallied support as a centrist with an independent streak, but the tight contest shows the difficulty GOP senators have appealing to Trump’s most ardent backers while also retaining support from more moderate voters.

The political landscape is quickly changing from six years ago, when most of these senators last faced voters. It’s a reminder of how sharply the political climate has shifted in the Trump era.

In Montana, Republican Sen. Steve Daines was trying to hold off Democrat Steve Bullock, the governor, in a state where Trump was popular.

Iowa Sen. Joni Ernst was fighting for a second term against Democrat Theresa Greenfield.

And in Alaska, newcomer Al Gross, a doctor, broke state fundraising records in part with viral campaign ads as he took on GOP Sen. Dan Sullivan.