As health care providers, we find ourselves on the verge of a new era in the treatment of chronic hepatitis C virus (HCV) infection. A number of directly acting antiviral agents are now in the latter stages of clinical development. The more promising candidates include direct inhibitors of the HCV nonstructural 3 protease, as well as both nucleoside and non-nucleoside inhibitors of the NS5B RNA-dependent RNA polymerase. Although these agents have demonstrated potent antiviral effect, monotherapy has been complicated by rapid virological breakthrough due to the selection of drug-resistant mutants. As for HIV and HBV, combination therapy will therefore be necessary. This brief review summarizes the current literature concerning resistance and directly acting antiviral agents, and identifies key challenges facing this emerging field.