Updated at 11:50 p.m. ET
Political novice Rand Paul rode support from tea party activists to a rout in, jolting the GOP establishment. Democratic Sen. Arlen Specter , a five-term incumbent offering experience to voters clamoring for change.
Another Democratic incumbent, Sen. Blanche Lincoln, failed to win the majority of votes in the Democratic primary. Lincoln iswith Lt. Gov. Bill Halter for her party's nomination.
In a fourth race with national implications,in a contest to fill out the final few months in the term of the late Rep. John Murtha in Pennsylvania. Each political party invested nearly $1 million in that contest and said the race to succeed the longtime Democratic lawmaker was something of a bellwether for the fall.
The conservative Paul, savoring his triumph over Secretary of State Trey Grayson, told supporters: "I have a message, a message from the tea party, a message that is loud and clear and does not mince words: We have come to take our government back."
But the same energy that helped Paul to victory presented problems to be handled carefully by the Republicans in the run-up to November, when control of both houses of Congress will be at stake.
Paul has said he might not support his fellow Kentuckian, McConnell, for a new term as party leader. And no sooner had Tuesday's results been posted than Richard Viguerie, a longtime conservative warrior, suggested McConnell step aside.
The far-flung races took place a little less than five months before the midterm elections. President Barack Obama backed incumbents in his party's races, but despite the stakes for his legislative agenda the White House insisted he was not following the results very closely.
Whatever the fate of the parties, public opinion polls - and the defeat of two veteran lawmakers in earlier contests - already had turned the campaign into a year of living dangerously for incumbents.
High unemployment, an economy just now emerging from the worst recession in generations and Congress' decision to bail out Wall Street giants in 2008 all added to voters' unease, polls said. In a survey released shortly before the polls closed, ABC said voter expectations for the economy had turned optimistic for the first time in six years. At that, only 33 percent of those polled said so in the network's polling, compared with 29 percent saying the opposite.
On the busiest primary night of the year so far, Specter lost to two-term Rep. Joe Sestak.
With nearly two-thirds of the precincts reporting, Sestak had 53 percent of the vote and Specter 47 percent.
Former Rep. Pat Toomey easily won the Republican nomination - six years after losing to Specter in a GOP primary.
In Oregon, Democratic Sen. Ron Wyden faced little opposition for nomination to a third full term.
In Kentucky, Paul had 59 percent of the vote with returns counted from 85 percent of the precincts, compared to 36 percent for Grayson, who had been recruited to the race by the state's dominant Republican, U.S. Senate Minority Leader Mitch McConnell.
In a Democratic primary that commanded far less national attention, Attorney General Jack Conway defeated Lt. Gov. Daniel Mongiardo and will face Paul in the fall.
In Kentucky, Grayson had the support of McConnell as well as other establishment figures. But Paul countered with endorsements - and the political energy that flowed along with them - from tea party activists, former Alaska Gov. Sarah Palin and Sen. Jim DeMint of South Carolina, a conservative eager to push his party rightward in advance of the broader fall campaign.
In an interview with The Associated Press, Palin called Paul's victory a "wake-up call for the country."
According to his website, Paul, 47 and an ophthalmologist, is a "career doctor, not a politician." He favors a balanced budget and paying off the national debt over time, but the website mentions no specifics.
He opposes all federal bailouts of private industry and government subsidies for alternative energy sources such as solar and wind power.
He has called Washington lobbyists a "distinctly criminal class" and favors banning lobbying and campaign contributions by anyone holding a federal contract exceeding $1 million.
The race marked the third time that tea party activists, a collection of disparate groups without a central political structure, have placed their stamp on Republican races.
Their votes at a Utah Republican convention helped deny a spot on the ballot to Sen. Bob Bennett, a conservative judged as not sufficiently so. And their backing helped propel one-time longshot Republican Marco Rubio to a lead in the pre-primary polls in Florida's Senate race, prompting Gov. Charlie Crist to quit the party and run as an independent.
In West Virginia, Democratic Rep. Alan Mollohan fell in a primary to an opponent who highlighted ethics issues.
Eager to avoid long-term fallout from a bruising primary, GOP leaders in Kentucky set a unity breakfast for Saturday.
The state's Senate seat is one of 10 or more that appear likely to remain competitive until Election Day, and one that Republicans can ill afford to lose if they are to make a serious run at challenging the Democratic majority. The seat is now held by Sen. Jim Bunning, but McConnell was so concerned about Bunning's ability to win a new term that he muscled the two-term lawmaker to the sidelines and recruited Grayson to run.
Paul, the son of Rep. Ron Paul, a former GOP presidential contender, entered the race with other ideas.
The far-flung races took place a little less than five months before midterm elections in which Republicans will challenge Democrats for control of both houses of Congress. President Barack Obama backed incumbents in his party's races, but despite the stakes for his legislative agenda the White House insisted he was not following the results very closely.
As if primaries weren't enough, both parties had other concerns.
Rep. Mark Souder, a conservative Republican from Indiana,, admitting he had had an affair with a woman on his congressional payroll. Democrats said his resignation would make the seat competitive in the fall.
And Democrat Richard Blumenthal, the Connecticut attorney general running for the Senate,. Republicans focused on the report, hoping it would increase their chances of winning the seat.