It is well documented that cytokines have critical functions in regulating immune responses and remarkably, the number of cytokines continues to expand. One large family factors that includes many interleukins and interferons binds related receptors termed the Type I and Type II families of cytokine receptors. These receptors activate Janus kinases (Jaks) and Stat family of transcription factors. The essential and specific function of Jaks and Stats is particularly well illustrated by human and mouse mutations. For instance, mutations of human Jak3 results in severe combined immunodeficiency. These mutations are of interest in that they provide clues to Jak structure/function. Additionally, patients with mutations that allow for partial expression of the protein may have nonclassical clinical presentations in which autoimmune features are prominent. There are also a number of mechanisms by which cytokine signaling is attenuated. One important family of inhibitory molecules is the SOCS family. The possibility that the various components of the cytokine signaling pathway could be targeted to produce novel immunosuppressive compounds will be discussed.