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.