Despite improvements to treatments for HCV infection, almost half of patients cannot be cured with standard combination therapy (pegylated interferon alpha and ribavirin). The HCV life cycle offers a number of potential targets for molecular therapy, and several specifically targeted antiviral therapies for HCV (STAT-Cs) are in preclinical and clinical stages of development. Evidence to date suggests that monotherapy with any antiviral drug is unlikely to eradicate HCV infection. Combination therapy with interferon and ribavirin is necessary for the augmentation of antiviral drug activity and/or prevention of drug resistance. Results from clinical trials carried out in the past few years on STAT-C agents in combination with standard therapy with peginterferon and ribavirin provide great promise of higher rates of sustained virological response and, potentially, shorter duration of therapy than standard therapy alone achieves. Although pegylated interferon and ribavirin are likely to remain a cornerstone of therapeutic regimens in the short term, combinations of antiviral drugs of different classes, possibly along with novel agents that target host factors and modulate viral replication or augment antiviral defenses, offer the eventual possibility of interferon-free regimens.