Signal transducers and activators of transcription (STATs) were discovered as mediators of type I interferon-induced gene expression. This family of transcription factors has been found in widespread signaling pathways, especially those involving cytokines regulating the immune response. Because a plethora and often confusing set of activators for STAT proteins was observed in cell culture models, it became important to define the physiologically relevant actions of these molecules. One approach to this question has been through the targeted disruption of STAT genes in transgenic mice. Now that all seven STAT genes have been disrupted, both the high degree of STAT selectivity as well as many surprising and unexpected complexities are beginning to be characterized.