The addition of hepatitis C virus (HCV) protease inhibitors (PIs) to interferon and ribavirin therapy has significantly improved the efficacy of treatment for HCV infection. However, for patients who do not respond to therapy, the selection of HCV variants with resistance to PIs is likely. Resistant variants, such as R155K and A156T/V, result in extensive cross-resistance to other HCV PIs. Despite the rapid and frequent appearance of PI-resistant HCV variants, the long-term clinical implications are unknown. In particular, progress in the development of other HCV antivirals, such as NS5A inhibitors, next-generation NS3 protease inhibitors, and NS5B nucleoside and nonnucleoside inhibitors, has provided a broad selection of potent antivirals such that interferon-free therapy is a reality. Promising results from early stages of interferon-free trials will be reviewed.