The ability to achieve a sustained virological response (SVR) to peginterferon (PEG-IFN) and ribavirin (RBV) depends on numerous host and virological factors, as well as adherence to a prescribed treatment regimen. Patients who have failed to achieve a SVR to PEG-IFN and RBV have limited options for retreatment. Emerging data from phase II and phase III clinical trials of direct-acting antiviral agents suggest that new therapeutic regimens will be available for many patients. Treatment with protease inhibitors such as PEG-IFN, RBV, ribavirin. and boceprevir, combined with PEG-IFN and RBV, has been shown to produce high rates of virological response in both prior relapsers and, to a lesser extent, prior non-responders. The benefits of these novel treatment regimens for each individual patient must be weighed against the side effects, costs and potential of developing viral resistance. Regulatory approval of telaprevir and boceprevir is expected to begin in mid-late 2011.