Direct-acting antiviral agents in combination with pegylated interferon (PEG-IFN) and ribavirin (RBV) significantly improve sustained virologic response rate and reduce duration of therapy among both treatment-naïve and treatment-experienced patients with genotype 1 chronic hepatitis C. One of the most important considerations with both boceprevir and telaprevir is the potential development of resistant variants with therapy. Patients with poor intrinsic responsiveness to interferon, and those with incomplete virological suppression on protease inhibitor therapy, appear to be at higher risk for resistance. In this article we will define antiviral resistance and review the data on both in vitro and in vivo resistance to protease inhibitors, concentrating on data on boceprevir and telaprevir. We will also explore the significance of resistant variants present at the baseline, as well as the fate of the resistant variants and the ways to minimize the development of resistance to protease inhibitors.