Current treatment of chronic hepatitis C virus (HCV) infection is based on the combination of pegylated interferon‐α and ribavirin. The recent development of direct‐acting antiviral (DAA) molecules that are active on HCV, together with in vitro and in vivo studies showing that these drugs may lead to the selection of resistant viruses if administered alone, has raised concerns that resistance may undermine therapy based on DAAs. A new standard‐of‐care treatment will soon be available for both treatment‐naive and treatment‐experienced patients infected with HCV genotype 1, based on a triple combination of pegylated interferon‐α, ribavirin, and a protease inhibitor (either telaprevir or boceprevir). With this therapy, most failures to eradicate infection in treatment‐adherent patients are due to an inadequate response to pegylated interferon‐α and ribavirin, in the context of a low genetic barrier to resistance of first‐generation protease inhibitors. This article reviews patterns of resistance to HCV DAA drugs in development, the mechanisms underlying treatment failure when these drugs are combined with pegylated interferon‐α and ribavirin, the consequences of treatment failure, and possible means of optimizing future therapies that use DAAs. (HEPATOLOGY 2011;)