ABC News projects Republicans will take control of the House of Representatives picking-up between 60 and 70 seats in a resounding rebuke to President Obama and the Democrats.
The GOP House victory would be the biggest gain for a party in a midterm since 1938, when Democrats lost 71 seats amid deep economic malaise during the Great Depression.
House Minority Leader and likely future speaker John Boehner was moved to tears when he addressed a crowd of supporters in Washington.
"With their voices and their votes, the American people are demanding a new way forward in Washington," Boehner said. "The people's priorities will be our priorities. The people's agenda will be our agenda. This is our pledge to America, this is our pledge to you."
The president called Boehner to congratulate him on the Republican's big win. Boehner's office released a statement saying the two men "discussed working together to focus on the top priorities of the American people, which Boehner has identified as creating jobs and cutting spending."
"That's what they expect," Boehner said. He thanked the president for the call.
From Virginia to Indiana, Florida to North Dakota, Democratic incumbents felt the wrath of an angry electorate, fueled by record turnout among conservative voters, exit polls showed.
Handfuls of first-term Democratic reps were ousted just two years after being swept to office on President Obama's coattails, while at least five Democratic House veterans were kicked out of office after each serving more than two dozen years.
The impending GOP victory heralds an end to the often embattled tenure of Speaker Nancy Pelosi, who made history in 2007 when she became the first woman to ever hold that rank, and forces dozens of Democratic reps to hand over the gavels -- and the offices -- of their powerful committees to their Republican rivals. Pelosi's office did not issue a statement.
With Pelosi's departure the stage is set for Ohio Republican Boehner, the son of a bar owner and one of 12 children who became president of a plastics company before entering politics, to become the next speaker.
"This election victory belongs to millions of Americans who stood up, spoke out and said 'enough is enough' and would no longer tolerate an imperial Congress that ignored the will of the people," said House Minority Whip Mike Pence of Indiana.
"Tonight was a referendum on the Obama agenda and the American people rejected it," said California Republican Rep. Darrrell Issa. "The American people have sent a clear and direct message to Washington that they want less spending, limited government and more accountability."
Sarah Palin reacted to the news that the GOP is projected to gain control of the House, calling it "an earthquake."
The Republicans' victory in the House will mark only the third time in 50 years that control of the chamber has changed hands.
A split balance of power in Congress will also make it much harder for President Obama and Democrats to advance their legislative agenda and increases the prospect of political gridlock on everything from taxes and spending to immigration.
Exit polling showed anxiety over the economy topped the list of voters' concerns Tuesday and compounded their near-record low approval of their government and the political parties, as seen in recent polls.
The GOP path to victory cut through many districts narrowly won by Democrats in 2008 and places where Republican John McCain carried the presidential vote.
First-term Democrat Tom Perriello of Virginia's fifth district lost his seat despite repeated campaign appearances on his behalf by President Obama. Virginia voters also ousted veteran Democrat Rep. Rick Boucher, who's served in Congress since 1983.
In Indiana, two of three GOP candidates in the state's most competitive races defeated their Democratic incumbent opponents, a key bellwether for a Republican take-over. And in South Carolina, voters made Republican Tim Scott the first African American Republican member of the House since J.C. Watts retired in 2003.
Cincinnati voters, who sent Democrat Steve Driehaus to Congress two years ago, were projected to send former seven-term Republican Rep. Steve Chabot back to Washington instead.
A deep anti-incumbent, anti-establishment mood has also affected veteran Democrats and liberal icons in blue districts, some of who have been in the political fights of their lives.
Missouri Democrat Ike Skelton, who chairs the House Armed Services Committee, and John Spratt of South Carolina, who chairs the House Budget Committee, both appeared poised to lose their jobs after more than two decades each in Congress.
Veteran Democrat Jim Oberstar of Minnesota, who heads the House Transportation Committee, was neck and neck with his Republican opponent as early returns still came in.
Massachusetts' Barney Frank, one of the most prominent Democrats in the House, and John Dingell of Michigan, the longest-serving U.S. Representative in history, have been threatened by Republican challengers this year but were projected to eek out wins in their districts.
Mounting the challenges to many Democratics incumbents across the country have been a colorful and diverse cast of Republican candidates including political rookies, grizzled veterans and Tea Party-backed conservatives. But only a handful were successful Tuesday.
Illinois pizza parlor owner Bobby Schilling defeated Democratic incumbent Rep. Phil Hare; New York opthamologist Nan Hayworthousted Democrat John Hall ; and, Arizona dentist Paul Gosar unseated incumbent Ann Kirkpatrick, whose reelection bid had hoped for turnout among Native Americans to carry her to another term.