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Dole was initially a heavy favorite for re-election, especially after several potential top-tier challengers such as Congressman Brad Miller, Governor Mike Easley and former Governor Jim Hunt all declined to compete against Dole.

Ultimately, Kay Hagan, a state senator from Greensboro, won the Democratic primary election against Jim Neal and became Dole's general election opponent.

Reports late in the campaign suggested that Dole suffered from Barack Obama's decision to aggressively contest North Carolina in the presidential election, while Hagan received substantial support from independent 527 groups lobbying / advertising against Dole, as well as the Democratic Senate Campaign Committee, which spent more money in North Carolina than in any other state during the 2008 election season.

Dole undertook an eight-day " ElizaBus " tour of the state in the days leading up to election day.