Dramatic progress is being made toward the development of less-toxic and simpler alternatives to the current standard-of-care therapy for chronic hepatitis C, which involves a combination of pegylated interferon (peg-IFN) and ribavirin (RBV). Several accessible viral targets have been identified and licensure of the most advanced clinical compounds can be anticipated within the next several years. However, the highly replicative nature of HCV infection, coupled with error-prone viral RNA synthesis and considerable genome diversity, pose extraordinary challenges to drug development. Peg-IFN is likely to remain a mainstay of therapy for the foreseeable future, or until such time that multiple direct-acting antiviral (STAT-C) inhibitors are available and shown to provide a sufficiently high barrier to resistance when used in combination.