Promising results have been observed with an investigational drug class for hepatitis C (HCV), the specifically targeted antiviral therapies for hepatitis C (STAT-Cs), when combined with peginterferon plus ribavirin (Peg-IFN/RBV). This class has the potential to increase sustained virological response (SVR) rates and reduce therapy duration in genotype 1 chronic HCV patients compared with Peg-IFN/RBV alone. However, because of the remarkable sequence variation in HCV (resulting from the high viral replication rate and intrinsically error-prone nature of HCV polymerase), variants with reduced susceptibility to STAT-Cs can occur naturally before treatment, usually at low levels, and can be selected in patients not responding to potent STAT-C treatment. This review first describes how resistance to a STAT-C can develop and then provides an overview of mutations that confer varying levels of resistance to STAT-Cs, which have been identified and characterized using both genotypic and phenotypic tools. We will discuss why an understanding of the selection of variants with reduced susceptibility to a treatment regimen may be important in optimizing the use of this new class of HCV therapy. Strategies for optimizing treatment regimens to increase response rates, and thereby minimize resistance, will be discussed. Finally, although resistance can be a consequence of not achieving an SVR on an initial regimen, there may be alternative treatment options for patients to achieve an SVR in the future. Future potential therapeutic strategies to address patients who do develop resistance to STAT-Cs are discussed, including combination therapy with multiple STAT-Cs with non-overlapping resistance profiles.