Cytokine signaling is dependent on the activation of intracellular molecules, including JAKs (Janus family kinases) and STATs (signal transducers and activators of transcription). Since the discovery of the SOCS (suppressor of cytokine signaling) family molecules in 1997, extensive investigation of these molecules has given important insights into the as yet unclarified regulatory mechanisms of cytokine signaling. Recent gene targeting analyses of SOCS molecules have revealed that they do indeed have essential roles in vivo (more specific than those expected from overexpression studies in vitro) in the negative regulation of various cytokines. Moreover, consistent with the pathological actions of cytokines in human diseases, recent lines of evidence also indicate that SOCS molecules are implicated in autoimmunity, allergy and cancers.