Chronic hepatitis C virus (HCV) infection is a pressing medical problem worldwide. Current therapy with pegylated interferon plus ribavirin (Peg-IFN/RBV) is associated with a poor risk benefit profile, a long treatment duration (48 weeks) and inadequate success rate (approximately 40-50%) of SVR (sustained viral response) in patients infected with genotype 1 HCV. This review is focused on recent clinical trial results with specifically targeted antiviral therapy for HCV (STAT-C) protease and polymerase inhibitors. In the past decade, anti-HCV drug discovery has focused first on targeting host factors required for viral replication and second on multiple HCV antiviral agents. Owing to the large number of HCV inhibitors currently in pre-clinical and clinical development today, we have focused on the most advanced compounds in the HCV polymerase and HCV protease inhibitor classes. Within each class, compounds will be used to illustrate some of the properties associated with inhibitors that bind to the active site of HCV polymerase, the active site of HCV protease (macrocyclic and linear ketoamide inhibitors) and allosteric polymerase inhibitors.