The choices couldn't be more different.
Reid, 70, is the bland, sometimes prickly Democratic powerhouse who tells Nevadans, "I'm just who I am." Angle, 60, is a fiercely committed small-government, low-tax crusader, an outsider even in the GOP, who says, "I am the tea party."
The former school teacher and legislator grabbed the nomination after a brutal primary in which her rivals depicted her as too extreme to appeal to independents who often cast the decisive votes in centrist Nevada. She benefited when one-time front-runner Sue Lowden was widely mocked for suggesting consumers use chickens to barter with doctors.
Unemployed freight worker Tina Immormino, 45, of Henderson, said she voted for Angle "because we definitely need change in government and Harry Reid has to go. Everyone in Washington has to go."
Reid emerges as the prohibitive front-runner.
Democrats are already depicting Angle as a loopy fringe figure, more caricature than politician. With plenty of money on hand and deep-pocketed allies, Reid and his supporters are expected to use TV ads to quickly define Angle in the populous Las Vegas region - home to about two of every three state voters - where she is not well known.
The Patriot Majority, funded in part by unions and run by Craig Varoga, a veteran Democratic operative who did a stint on Reid's staff years ago, launched a website ridiculing Angle and calling her positions "completely out of step." Democratic Senatorial Campaign Committee Chairman Robert Menendez said Angle "cares more about promoting a strict social doctrine than helping grow the state's economy."
With virtually all of the vote counted, Angle had 70,420 votes, or 40 percent, easily outdistancing Sue Lowden, who tallied 45,861, or 26 percent, according to unofficial returns.
Angle said the campaign "is about taking back America."
"We are going to dump Harry Reid," she told cheering supporters.
Angle wants to phase out Social Security for younger workers, eliminate the Education Department and once suggested that alcohol should be illegal. While in the Legislature, Angle wanted inmates to enter a drug rehabilitation program devised by Scientology founder L. Ron Hubbard, an idea she still defends.
Reid breaks with her on a host of issues. In an interview, he called Social Security "the most important social program in the history of the world." And while Reid blocked the proposed Yucca Mountain nuclear dump, Angle wants to expand the nuclear industry in Nevada.
With Nevada suffering with 13.7 percent unemployment, Reid said the campaign would focus on jobs, including green energy.
"Why shouldn't the people of Nevada be concerned and upset. I'm as concerned and upset as they are," Reid said. "We've got a lot of work to do."
It's not clear if the Republican establishment that Angle bucked throughout her legislative days will turn around and embrace her.
She needs money, quickly. And she will have to rapidly expand her campaign team; she ran her primary operation out of her home, with a brain trust of two other people: her husband Ted and press secretary Jerry Stacy.
"It looks like good news for Harry Reid," said University of Nevada, Las Vegas, political scientist David DaMore. "She has pretty well defined herself as a niche candidate. How does she break out of that mold to a broader audience?"
In a statement, Republican National Committee Chairman Michael Steele promised that Angle would get the support from the national party she needs to win.
Reid knows the race won't be a walkover - he's been compared to former Senate Democratic leader Tom Daschle, whose support for a liberal-leaning agenda in Washington cost him re-election in his conservative home state of South Dakota in 2004.
But he's now running about even with any Republican nominee, polls have found. A string of earlier polls showed Reid losing to a lineup of possible Republican nominees, but he has benefited from missteps and infighting in the GOP field.
Reid has never been a beloved figure in his home state. But he has survived close elections before, and he is preparing for a bruising fight this year. The casino industry and labor unions are betting on him, he has a substantial list of Republican supporters, and he is on his way to raising an unprecedented $25 million for the race.
In the state's U.S. House races, Democratic Rep. Shelley Berkley will defend her seat in November against Republican Kenneth Wegner in Las Vegas' 1st District, and Democratic Rep. Dina Titus will face Republican Joe Heck in November in the 3rd District. Republicans nominated Rep. Dean Heller in the 2nd District, but Democrats Nancy Price and Ken McKenna were in a tight contest for the Democratic nomination.
More CBSNews.com Coverage of Tuesday's Primaries:
Winners: | | Meg Whitman | Carly Fiorina | Sharron Angle | Roundup
Women Win Big on Primary Day
Interactive Map: CBS News Campaign 2010 Race Ratings