Raese defeated a crowded field of Republicans and becomes part of the GOP quest to dismantle the Democratic Senate majority as high unemployment and the slow economic recovery take a toll on their political prospects this fall.
In Louisiana, scandal-tainted Republican U.S. Sen. David Vitter easily beat two little-known challengers and will meet Democratic Rep. Charlie Melancon, who won his party's primary, in November.
Vitter survived a 2007 prostitution scandal after he admitted an unspecified "serious sin" after his phone number appeared in the records of a Washington prostitution ring. He has also shrugged off fresh questions about his judgment in allowing an aide to remain on his staff for more than two years after a violent attack on a woman police identified as his ex-girlfriend.
With little competition from his own party, he and Melancon have already engaged in attacks.
"There is a clear choice in this election, and as we educate voters about my positive plans for putting Louisiana first and contrast it with David Vitter's hostility toward women, veterans and Louisiana families, I know we'll win," Melancon said.
Vitter said in a statement that Melancon was too liberal.
"Louisiana voters will get to choose between the current Obama policies of endless bailouts, failed stimulus, massive debt, and government-dominated health care, represented by Charlie Melancon, or the common sense conservative alternatives I've been advocating," he said.
The primary in West Virginia was hastily called after Byrd, a 92-year-old Democrat elected to a record ninth term in 2006, died June 28.
Manchin won his seventh-straight statewide campaign. He enjoys high approval ratings and was seen as a comforter-in-chief to victims' families following the Upper Big Branch mine explosion, which killed 29 workers in April, and the Sago mine disaster in 2006.
"I'm running for the U.S. Senate to represent all the people," said Manchin, 63. "It's going to be a sprint now and we're prepared."
Manchin's support from coal and utility industries - which have provided more than a quarter of the $1.2 million he has raised since declaring his candidacy last month - may help him overcome national GOP attempts to paint him as a liberal who will side with President Barack Obama's administration.
Obama lost West Virginia in 2008, and his energy and environmental policies are deemed anti-coal in the nation's second-largest coal producing state. Democrats desperately need to hold the Senate seat in West Virginia, a state that Republican nominee John McCain won handily with 56 percent of the vote.
The 60-year-old Raese, who lost to Byrd in 2006, has been pumping money into a television and radio ad campaign to bolster his name recognition.
Raese owns a steel fabricating business, a limestone company and is part owner of a statewide radio network and Morgantown newspaper. He spent at least a half-million dollars of his own money into his latest campaign.
Mountain Party candidate Jesse Johnson is also vying for the seat in November.