Type I interferons (IFNs) are a family of cytokines specialized to coordinate immunity to viruses and other intracellular infections. In the past several years, many of the receptors and signaling pathways that link pathogen detection to induction of type I IFNs have been identified and characterized. An integrated picture has emerged in which type I IFNs have essential functions in several seemingly disparate processes: they restrict viral spread by engaging machinery that ultimately cripples and kills infected cells, yet they are also positively linked to the activation and expansion of lymphocytes that are important for control of intracellular infections. These advances highlight the context-specific actions of type I IFNs and clarify the multiple points at which they are integrated into both innate and adaptive immunity.