HCV infection is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. HCV persists in more than 70% of exposed individuals and, therefore, must have evolved mechanisms to evade the antiviral immune response of the host. The HCV protease NS3/4A can cleave and inactivate key components of important sensory pathways that lead to the induction of IFN-β upon viral infection in cells. Despite this finding, the endogenous interferon system is constantly activated in the liver of a substantial group of patients with chronic hepatitis C. However, the induced interferon-stimulated genes are ineffective in clearing the infection. Furthermore, patients with a preactivated interferon system do not respond to the current therapy with PEGylated IFN-α and ribavirin.