Direct acting antiviral agents have revolutionized the treatment of chronic infection with hepatitis C virus (HCV), but further improvements are needed to meet the public health goal of controlling HCV worldwide. Shortened courses of therapy might reduce the high costs that present a major barrier to large-scale treatment programs and improve options for treating HCV in marginalized, high-prevalence populations with potentially poorer adherence to treatment. In developing intervention strategies, it is important to differentiate virologic failure (most often owing to virologic relapse) from poor adherence, because these problems require different responses.