A family of cytokine-inducible SH2 proteins (CISs) has recently been identified and the number of family members is growing. In this family, the central SH2 domain and C-terminal (about 40 amino acids) (CIS homology domain; CH domain) are well conserved, while N-terminal region shares little similarity and varies in length. Most of them appear to be induced after stimulation with several different cytokines and at least three of them (CIS1, CIS3 and JAB) negatively regulate cytokine signal transduction by various means. Forced expression of CIS1 inhibits STAT5 activation by binding to cytokine receptors, whereas CIS3 and JAB directly binds to the kinase domain of JAKs, thereby inhibiting tyrosine kinase activity. Therefore, these CIS family members seem to function in a classical negative feedback loop of cytokine signaling. They may also be involved in suppression between cytokines frequently found in immune and inflammatory responses. JAB is found to inhibit interferon signaling, suggesting that elevated expression of JAB is involved in interferon-resistance. The mechanisms by which these inhibitors of cytokine signal transduction exert their effects and their physiological functions are crucial issues which need to be and will be addressed in the near future.