The high-affinity binding interactions between interferons (IFNs) and their cognate cell surface receptors lead to the activation of receptor-associated Janus protein tyrosine kinases (Jaks) and subsequent phosphorylation and activation of a group of transcription factors, the signal transducers and activators of transcription (Stats). Upon IFN-induced activation, these Stat proteins form homodimeric and heterodimeric complexes that translocate to the nucleus and bind specific elements within the promoters of IFN-stimulated genes (ISGs). In addition to the well-studied IFN-induced ISG factor 3 (ISGF3) and Stat1:1 complexes, IFNs induce the formation of a number of other Stat-containing complexes, including Stat3:3 and Stat5:5 homodimers, as well as Stat2:1 and Stat5:CrkL heterodimers, that also mediate gene transcription. Moreover, emerging evidence suggests that particular amino acid residues within the individual Stat proteins contribute to different aspects of Stat function. These residues modulate the transcriptional activation potential of Stat-containing complexes and thereby influence the expression of ISGs. Indeed, the Stat proteins function in a multifaceted manner to regulate the expression of proteins that mediate IFN responses.