Treatment of chronic hepatitis C virus (HCV) infection has substantially evolved over the past decade after the Consensus Conference organized by the European Association for the Study of the Liver in 1999. Since then, the standard of care (SOC) for patients with chronic hepatitis C has been the combination of pegylated interferon (pegIFN) alpha-2a or -2b and ribavirin. In patients infected with HCV genotype 1, by far the most frequent HCV genotype worldwide, such treatment leads to a cure of infection in only 40% to 50% of cases. Several factors have been identified to play a role in the outcome of therapy, including the treatment schedule, disease characteristics, viral, and host factors. Human genetic factors have been identified by a recent landmark discovery. However, these factors only partly explain the ability of IFN and ribavirin therapy to cure HCV infection. Several studies have demonstrated that, in non-responders, interferon-stimulated genes were up-regulated prior to therapy through unclear mechanisms. These findings, together with clinical, biochemical and histological data, may help better identify responders before starting therapy. This becomes particularly important as the standard treatment is physically and economically demanding. The future treatment of patients infected with HCV genotype 1 will be based on the combination of pegIFN and ribavirin with a protease inhibitor, telaprevir or boceprevir. Promising results of this triple combination in phase III clinical trials have been recently reported at the Liver Meeting 2010. With this therapy, higher cure rates will be achieved, but specific issues will be raised, such as the emergence of resistance to the protease inhibitors. The goal of this review is to discuss mechanisms involved in the non-response to current and future standard treatments.