Successful host defense against viruses depends on rapidly mounted defense mechanisms, which include the release of type I interferons (IFN)α/β and the transcription of IFN-stimulated genes. IFN limits viral replication and activates adaptive immunity. Much progress has now been made in delineating how the type I IFN response is triggered upon infection by different viruses. Progress in this regard relates to the identification of distinct families of pattern recognition receptors involved in the detection of viral nucleic acids, the discovery of adapter molecules, which couple signaling from these receptors to downstream effectors, and the characterization of key kinases responsible for the phosphorylation-induced activation of the IFN regulatory factors that control IFN gene transcription. In turn, we are learning that viruses encode a diversity of sophisticated mechanisms to block IFN induction at each of these levels and/or counteract IFN activity, thereby supporting viral replication and neutralizing the therapeutic action of IFNs.