The interferons are pleiotropic cytokines that are induced in response to virus infection and act in a paracrine fashion to elicit an antiviral state in nearby cells. Binding of interferons to their cell surface receptors induces a tyrosine kinase signaling cascade that leads to the activation of latent cytoplasmic signal transducer and activator of transcription (STAT) factors. Activated STATs then translocate into the nucleus and are targeted to conserved promoter-enhancer sites to induce the transcription of interferon-responsive genes that encode for proteins with potent antiviral, growth-inhibitory, antitumor, and immunomodulatory properties. Although the signaling and activation phase of the interferon response has been well characterized, several recent findings have further clarified the cellular events that immediately follow STAT activation, including the identification of the amino acid signals that regulate the subcellular distribution of interferon- signaling proteins. To achieve their full transcriptional capacity, members of the STAT family of transcription factors have been shown to require interactions with an assortment of nuclear transcriptional co-activator proteins. A number of the STAT co-activator protein partners have only been identified recently. Some of these interactions suggest cross-talk with other signaling pathways, thereby reaffirming the far-reaching, yet undiscovered, properties of interferons.