Evaluation of: Meylan E, Curran J, Hofmann K et al.: CARDIF is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437(7062), 1167–1172 (2005). The induction of type 1 interferon (IFN) sits at the heart of the host immune response against infecting pathogens. When in contact with the cell surface, RNA viruses may induce an intracellular signal that leads to nuclear factor activation, production of type 1 IFNs, the arrest of virus replication and the initiation of an inflammatory response. Activation of toll-like receptors by double-stranded RNA has been thought of as an important event in virus-induced intracellular signaling leading to IFN induction. However, the RNA helicase retinoic acid inducible gene (RIG)-I may bind double-stranded RNA and trigger IFN production in a toll-like receptor-independent manner. Many RNA viruses, including hepatitis C virus, have developed mechanisms to fight back and block the induction of IFN. Meylan and colleagues have identified an important element of the RIG-I-dependent response that may be targeted and destroyed by the nonstructural (NS)3/4A HCV protease and block intracellular signaling and IFN production. Their finding may help us to identify clearly how RNA viruses interfere with the host immune response and the relevant role of viral proteases in generating a productive virus infection.