Specter was backed by the White House -- although neither Obama nor Vice President Joe Biden campaigned with him in recent days -- as well as other heavy hitters in the state such as Rendell.
Those supporters who now have to switch their allegiance to Sestak cautiously congratulated both candidates while quickly aligning themselves behind the new Democratic candidate for the seat.
"Congressman Sestak and Sen. Specter both campaigned tirelessly across the Keystone State in support of President Obama's efforts to help middle-class Americans. I congratulate them both on a hard-fought campaign," Democratic National Committee chairman Tim Kaine said in a statement.
Sen. Robert Menendez, D-N.J., chairman of the Democratic Senatorial Campaign Committee said both men deserved credit for "waging thoughtful, spirited campaigns."
On the Republican front, former congressman Toomey secured the GOP nomination, as expected, and will face Sestak in the midterm election.
"I have a message, a message from the Tea Party," Paul said in a speech to his supporters Tuesday night in Kentucky. "We've come to take our government back.
"Washington is horribly broken," he added. "I think we stand on a precipice. We are encountering a day of reckoning and this movement, this Tea Part movement, is a message to Washington that we're unhappy and we want things done differently."
Kentucky Republican Trey Grayson was backed by some of the most powerful Republicans in Washington, including former vice president Dick Cheney and Senate Minority Leader Mitch McConnell, R-Ky., who especially handpicked Grayson. But Paul, a rookie politician, has been a supporter of the Tea Party since its inception and also secured the support of another Tea Party favorite, Palin.
McConnell congratulated Rand and promised to back him in the race against Democrats.
"Dr. Paul ran an outstanding campaign which clearly struck a chord with Kentucky voters and I congratulate him on his impressive victory," McConnell said in a statement. "Now Kentucky Republicans will unite in standing against the overreaching policies of the Obama administration. We are spiraling further into unsustainable debt and Kentucky needs Rand Paul in the U.S. Senate because he will work every day to stop this crippling agenda."
Outside polling stations Tuesday, Paul's supporters cheered and waved his signs.
"I did not vote for any incumbent. Any incumbent I want out. We need change, period," resident Rickie Eadens told ABC News.
Another voter, Brad Leix, said he voted for Paul because he is not a Washington insider.
"I'm just tired of the government insiders," he said. "You've got certain people who've been in office for so long. We need some outside views that aren't afraid to rock the boat a little bit. So, I think that people like him will be good for the country."
A spokesman for the Kentucky Secretary of State's office told ABC News that turnout was low and absentee voting was down 16 percent from the previous primary.
Kentucky's liberal Attorney General Paul Conway won the Democratic nomination. Conway was running against the more conservative Lt. Gov. Dan Mongiardo, who opposed Obama's health care plan.
In the western Pennsylvania special House election to replace the late Rep. John Murtha, Republican Tim Burns called and conceded the race to Democrat and former Murtha aide Mark Critz.