Type I IFNs induce gene expression through Stat1 and Stat2, which can in turn associate either to form Stat1 homodimers or the transcription factor ISGF-3. Stat1 homodimers also transduce signals for IFN-γ. To explore the unique properties of Stat2 and ISGF-3 in type I IFN signaling, its gene was targeted for deletion. Stat2 null mice exhibit a number of defects in immune response. This includes an increased susceptibility to viral infection and the loss of a type I IFN autocrine/paracrine loop, which in turn regulates several aspects of immune response. Intriguingly, Stat2-deficient fibroblasts exhibit a more significant defect in their response to type I IFNs than macrophages, highlighting tissue-specific differences in the response to this family of ligands.