Democrats had difficulty recruiting top tier candidates against the popular Specter. Among the Democrats to decline to run for the nomination were Treasurer (and former Republican) Barbara Hafer, Public Utilities Commissioner John Hanger, real estate mogul Howard Hanna, State Representative (and also former Republican) John Lawless, and State Senator (and future Congresswoman) Allyson Schwartz.
Congressman Hoeffel ended up running unopposed for the Democratic nomination. Software businessman Charlie Crystle was considered a strong possible candidate, but he dropped out before the election.
Specter faced a primary challenge from RepresentativePat Toomey. Despite the state Republican Party's strong history of embracing a moderate philosophy, the influence of conservatism among rank-and-file members had been steadily growing for decades; because of his liberal social views, Specter was often considered to be a "Republican in Name Only" by the right. Although Specter had a huge fundraising advantage, Toomey was aided by $2 million of advertising from the Club for Growth, a conservative political action committee that focuses on fiscal issues and targets moderate Republican incumbents. Toomey criticized Specter as a spendthrift on economic policy and as out of touch with his own party on social issues. Although Toomey had difficulty with name recognition early in the campaign, he built huge momentum over the final weeks preceding the primary, and Specter appeared to have transitioned from having a comfortable lead to being behind his challenger 
Specter received a huge boost from the vocal support of President George W. Bush; most of the state's Republican establishment also closed ranks behind Specter. This included Pennsylvania's other U.S. Senator, Rick Santorum, who was noted for his social conservative views. Many Republicans at the state and national level feared that if Toomey beat Specter, he wouldn't be able to defend the seat against his Democratic opponent.
For Democrats, hope of winning the election centered on Toomey's defeat of Specter. However, after the challenge from the right failed, enthusiasm from the party establishment waned and Hoeffel had difficulty matching the name recognition and fundraising power of his opponent  Despite contempt from conservatives, Specter enjoyed high levels of support from independent voters and, as in previous elections, a surprisingly large crossover from Democratic voters. Even in the areas in which Toomey performed best in the Republican primary (mainly the state's conservative, rural center), Specter performed well. Except for his large margin of victory in almost uniformly Democratic Philadelphia, Hoeffel was crushed at the polls; his only other wins came by close margins in three metro Pittsburgh counties; although President Bush proved to be unpopular in the state, voters were not willing to abandon Specter over party affiliation.