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Anger over government spending and economic weakness gave rise to the Tea Party, a loosely organized conservative movement that backs smaller government and lower taxes.
"People are just fed up with the Obama administration - that 'hope and change' thing," said retail manager Nadine Leder in Milwaukee, Wisconsin, who planned to vote for Republicans.
In a final push, Obama gave Election Day interviews to radio stations in several battleground states.
"Things have gotten better over the last two years," he told KPWR in Los Angeles. "We can only keep it up if I've got some friends and allies in Congress and statehouses."
In the bellwether state of Ohio, former President Bill Clinton called radio stations to help fellow Democrats.
Obama will hold a news conference at 1 pm EDT (1700 GMT) on Wednesday to talk about the post-election landscape.
Gridlock and market cheer
Republican candidates have pushed an agenda of spending cuts and at least a partial repeal of Obama's healthcare and Wall Street reforms, but Obama could veto their efforts.
"We can expect very substantial Republican gains leading to super-gridlock for two years," said University of Virginia political science professor Larry Sabato.
Some research suggests that stocks languish when power is split in Washington, but they have risen in recent months on the promise of a more business-friendly Congress.
That trend continued on Tuesday, with the greatest gains in sectors expected to benefit from a shift in power, though many forecast a sell-off in the days ahead. Health insurer stocks rose, with an index of the sector gaining 2.7 percent as investors bet that Obama will have to battle to keep his healthcare reform in place.
Republicans, who lost control of Congress in 2006, have said this election is more about rejection of Democrats than an endorsement of their party.
Representative John Boehner, who would take over as House speaker if the Republicans win control of the chamber, has said he would govern more cautiously than previous speakers.
Voters on Tuesday also will weigh in on a variety of topics: in California, for example, they could approve a measure that would legalize possession of marijuana.
In perhaps the country's most high-profile race, Senate Democratic leader Harry Reid is embroiled in a neck-and-neck re-election fight with Tea Party favorite Sharron Angle in Nevada. The race could hinge on how many voters pick the "none of the above" option on the Nevada ballot.