With the approval of the first hepatitis C virus (HCV) protease inhibitor in 2011, we are currently in the midst of a paradigm shift in hepatitis C treatment. Within the next three years, the vast majority of hepatitis C patients in Western countries will likely receive a completely different drug therapy than they currently do. The field of hepatitis C treatment is rapidly evolving. Given the ongoing changes in this field, treatment of patients with hepatitis C will become extremely challenging in 2013. Several questions remain controversial.1 Which patients should be treated promptly with the medications they already have? Which patients can wait until interferon-free therapies become available? When will interferon-free therapies become available, and will the new drugs be effective and well tolerated? What are the costs of interferon-free therapies? Are there other alternatives that could further improve the efficacy of the drugs currently used? IFN-α has been the cornerstone of antiviral therapy for chronic hepatitis C for more than two decades, with sustained virologic response (SVR) rates ranging from 30-90% depending on HCV genotype, stage of liver disease progression, and host genetic background.2 However, because IFN-α-containing therapy is associated with a range of adverse events, IFN-α is used for the treatment of only a small number of HCV-infected individuals Unlike most other persistent viral infections, HCV infection is potentially curable. HCV completes its life cycle in the cytoplasm alone (no nuclear phase exists), and therefore, effective inhibition of viral replication can cure HCV-infected cells in the absence of drug resistance. Therefore, one obvious way to improve hepatitis C therapy is to use a combination of novel direct antiviral agents (DAAs) that target different stages of the HCV life cycle.