The addition of hepatitis C virus NS3 protease inhibitors to interferon-based regimens has dramatically improved response rates. Despite these improvements treatment is now more complex, associated with increased side effects, and has the potential to select resistant variants in those who are not cured. This article discusses the virologic underpinnings for the development of hepatitis C virus–resistant variants (with a focus on telaprevir and boceprevir) and their impact on therapeutic success. Interim guidance on the use of resistance testing and management is provided based on the limited data. Finally, resistance considerations for other classes of inhibitors and the rapidly approaching interferon-free therapeutics regimens are offered.