During the past decade, the receptors for the type I (alpha, beta, and omega) and type II (gamma) interferons (IFNs) have been identified. The IFN-gamma receptor consists of two transmembrane chains, IFN-gammaR1 and IFN-gammaR2, both of which are required for activity. The IFN-gammaR1 chain binds the IFN-gamma ligand, whereas the IFN-gammaR2 chain is required for signal transduction. After ligand binding, Jak1 and Jak2 kinases are activated by phosphorylation and then phosphorylate the IFN-gammaR1 chain, which serves as the recruitment site for Stat1alpha (signal transducers and activators of transcription). After recruitment to the phosphorylated IFN-gammaR1 chain, Stat1alpha is then phosphorylated and released to form a Stat1alpha dimer that represents the active transcription factor for IFN-gamma-induced genes. An analogous paradigm exists for the type I IFN (IFN-alpha/beta) receptor. This receptor appears to consist of two chains, IFN-alphaR1 and IFN-alphaR2, which can be present in different forms. Thus, the IFN-alphaR1 chain is present as the full chain (IFN-alphaR1a) and as a splice-variant (IFN-alphaR1s) lacking exons IV and V; the IFN-alphaR2 chain exists in soluble, short, and long forms (IFN-alphaR2a, IFN-alphaR2b, and IFN-alphaR2c, respectively). Most likely, the IFN-alphaR1a and IFN-alphaR2c chains represent the predominantly active form. After ligand binding of IFN-alpha, IFN-beta, or IFN-omega species, Tyk2 and Jak1 kinases are recruited to the receptor complex and activated. The activation results in the subsequent recruitment of Stat1 (Stat1alpha and Stat1beta) and Stat2, which form a Stat1/Stat2 heterodimer after their phosphorylation. The active transcription complex IFN-stimulated gene factor-3 is formed by the association of the Stat1/Stat2 heterodimer with the p48 protein. The active IFN-stimulated gene factor-3 binds to the promoter elements of type I IFN-induced genes to initiate their transcription. Although the overall motif appears clear, there is much complexity in these interactions in that the various type I IFNs exhibit different interactions with the receptor components. Apparently, each of the IFN-alpha species exhibits a different pattern of receptor interactions that reflects their different biologic activities and will likely explain the existence of this large family of IFN-alpha species, IFN-beta, and IFN-omega that all interact with the same basal receptor.