Virus research of the past decades showed that the vertebrate type I interferon (IFN) system is in principle capable of slowing down the replication and spread of most if not all viruses at early stages of infection. However, influenza viruses and other viral pathogens have evolved gene products to subvert this innate defense to enable efficient reproduction and thereby cause disease. Inhibition of type I IFN also impairs adaptive immune reactions as those cytokines function in the development of pathogen-specific cellular immunity. This article highlights the recent progress in our understanding of key interactions of influenza viruses with the type I IFN defense, which are central to viral virulence. A main focus is on corruptions of IFN-dependent antiviral functions mediated by the cellular receptors RIG-I and PKR and their blockade by the viral NS1 protein.