Vitter faced a potentially serious challenge in the Republican primary as well as the general election. Lieutenant GeneralRussel L. Honoré, who is best known for serving as commander of Joint Task Force Katrina responsible for coordinating military relief efforts for Hurricane Katrina-affected areas across the Gulf Coast was allegedly mulling over whether or not to challenge Vitter in the Republican Primary.Tony Perkins, a former Louisiana state representative and current president of the socially conservative Family Research Council, acknowledged interest in running against Vitter because of the prostitution scandal. Nonetheless, Perkins decided not to run; Perkins endorses Vitter for reelection.
Some speculated that Vitter's reelection might have become complicated, by the prostitution scandal revealed in 2007, but he continued to lead in aggregate polling against potential opponents.
Following a movement to draft him into the race,John Cooksey, a former U.S. Representative, appeared poised to put together a challenge, planning on spending $200,000 of his own money. Cooksey, however, pulled back and did not qualify.
On August 27, 2009, Congressman Charlie Melançon announced his intentions to run for Senate in 2010. Melançon, who has been representing Louisiana's 3rd Congressional District since 2005, released the announcement to his supporters, saying that "Louisiana needs a different approach, more bi-partisan, more disciplined, more honest and with a whole lot more common sense." Melancon has been a leader of the Blue Dog Coalition, a group of fiscally conservative Democrats who aim to lower the deficit and reform the budget.
In the weeks before the election a major concern for Vitter's camp was possibly voter apathy about the race. For example, publisher Rolfe H. McCollister Jr., in his Greater Baton Rouge Business Report, endorsed fellow Republican Jay Dardenne over Democrat Caroline Fayard in the simultaneous race for lieutenant governor of Louisiana, but then explicitly made "no endorsement" for U.S. Senate:
I have talked with a number of voters who are just not very excited about this race—the candidates or the tone. I'm not either. You're on your own here.
Melancon claimed “In August, Melancon challenged Vitter to a series of five live, televised town hall-style debates across the state. In his 2004 campaign for Senate, Vitter committed to five live, televised debates. Since Melancon issued the challenge, Vitter and Melancon have been invited to a total of seven live, televised debates. Vitter has only accepted invitations to debates hosted by WWL-TV and WDSU-TV, both in New Orleans.”