The Tea Party's Rand Paul has defeated Republican establishment favorite Trey Grayson in the GOP Senate primary poll in Kentucky, partial results show.
With 43% of precincts reporting, Mr Paul had 60% of the vote to Mr Greyson's 36%.
Voters in several other US states are also deciding on party candidates for November's mid-term elections.
The outcome of these primary ballots will be seen as a key indicator of the volatile political mood in America.
In Arkansas and Pennsyvlania, incumbent Democratic Senators Blanche Lincoln and Arlen Specter are facing strong challenges from within their party.
In the Republican race in Pennsyvlania, Pat Toomey won the nomination by beating activist Peg Luksik.
Polls suggest anti-incumbent sentiment is rife across the US.
Many voters are concerned that the federal government is doing too little to foster economic recovery and cut wasteful spending, analysts say.
President Barack Obama visited the swing state of Ohio, which has suffered badly in the downturn, to defend the efforts of Democrats in Congress to bolster the economy and create jobs.
"I know it's still tough, I know a lot of times the future still feels uncertain," Mr Obama told about 200 workers at a steel plant in the town of Youngstown.
"But I will tell you one thing: It's people like you, people in towns like Youngstown all across America that I'm thinking about every single day when I go to the Oval Office."