In Kentucky, voters opted for a conservative Tea Party newcomer in the Republican Senate primary over a handpicked Republican favourite.
Elsewhere, veteran senator Arlen Specter saw his bid for a sixth term ended yesterday with a loss to fellow Democrat Joe Sestak in Pennsylvania's primary vote, while two-term Democratic senator Blanche Lincoln also struggled in Arkansas after failing to win the necessary majority of the Senate primary vote.
Conservative Rand Paul easily won the party nomination over secretary of state Trey Grayson in a Kentucky race seen as an early test of the loosely organised Tea Party movement, a grass-roots section of the Republican Party that is pulling it to the right
Mr Paul, a doctor and son of libertarian Republican Representative Ron Paul, rode a wave of voter anger with the help of Tea Party activists who oppose runaway federal spending and favour more limited government.
"We have come to take our government back," he told supporters in Bowling Green, Kentucky. "This Tea Party movement is a message to Washington that we are unhappy and we want things done differently."
Mr Paul will face state attorney general Jack Conway, who won the Democratic primary, in November.