Senate minority leader Mitch McConnell, a Kentucky Republican, will face a 2014 election challenge from popular Democratic Secretary of State Alison Lundergan Grimes.
At a press conference on Monday in Frankfort, the state capital, Grimes said McConnell is vulnerable to defeat.
"Kentucky is tired of 28 years of obstruction ... tired of a senior senator that has lost touch with Kentucky issues, voters and their values," said Grimes.
A poll in late May by the Democratic firm Public Policy Polling found McConnell and Grimes tied at 45 percent each. The poll also showed McConnell with a 44 percent approval and 47 percent disapproval rating.
McConnell immediately fired back in a statement accusing her of pursuing a liberal agenda.
"Accepting the invitation from countless Washington liberals to become President (Barack) Obama's Kentucky candidate was a courageous decision by Alison Lundergan Grimes and I look forward to a respectful exchange of ideas," he said in statement.
He said Grimes supports a war on the coal industry and Obama's healthcare reform, which McConnell has tried to repeal.
Republicans are expected to try to tie Grimes to Obama, who lost Kentucky in the presidential election last year.
"Just last year, Alison Lundergan Grimes stood proudly at the Democratic National Convention to nominate Barack Obama, who has followed through on his promise to destroy the coal industry," said a statement by the National Republican Senatorial Committee.
She downplayed concerns about McConnell's vaunted fund-raising ability and name recognition.
"I was an underdog in the secretary of state race and I am no stranger to being an underdog," she said.
Grimes, 34, the daughter of a former state party chairman, received more votes in the 2011 election than any other Kentucky Democrat running for a major statewide office.
She announced her decision to take on McConnell, age 71, about three months after actress and Democratic activist Ashley Judd, who had been wooed by some in that party, decided against running against McConnell.
Kentucky has a history of electing moderate Democrats to statewide office. In addition to Grimes, the state has a Democratic governor, attorney general and treasurer. It is more Republican at the federal level. All but one of Kentucky's members of Congress are Republican, and its other U.S. senator is Rand Paul, a conservative Republican.
McConnell was elected Republican leader in 2006. He first won election to the U.S. Senate in 1984, defeating a long-time incumbent to become the first Republican to win a statewide Kentucky race since 1968.
Democrats hold a 52 to 46 majority in the U.S. Senate with two independents usually voting with the Democrats.
(Reporting by Tim Ghianni; Writing by Greg McCune; Editing by Steve Orlofsky)