Despite recent improvements in the treatment of patients who have chronic hepatitis C, a large proportion of patients do not achieve viral clearance. Treatment regimens are also costly, associated with significant morbidity, require substantial patient commitment, and are not appropriate for all patients. Therefore, it is important to maximize and enhance current therapeutic approaches and to investigate new approaches and therapies. Because the ability to maintain adherence to current treatment is associated with higher sustained virologic response rates (particularly in patients infected with genotype 1), strategies directed at patients and support staff to promote treatment adherence are important. Other strategies to enhance current therapy include alternative interferons (IFNs)/cytokines and new IFN delivery systems. Current therapy may also be enhanced by new ribavirin (RBV) analogs with an improved safety profile or by the addition of other immunomodulatory agents such as inosine 5'-monophosphate dehydrogenase inhibitors, histamine dihydrochloride, thymosin alfa 1, and amantadine. Some of these agents have demonstrated promising results, although further evaluation is required. Greater knowledge of the molecular biology of the hepatitis C virus (HCV) holds promise for the development of targeted therapies such as specific inhibitors of HCV polymerase, protease, or helicase, as well as therapeutic vaccines. Other potential molecular-based therapies include antisense oligonucleotides, ribozymes, and short interfering ribonucleic acid (RNA) molecules. Therapies aimed at reducing or preventing the development of fibrosis are also under investigation. Multiple-drug regimens will likely be required to enhance viral clearance and reduce viral resistance, while providing greater tolerability.