Multiple lines of evidence have revealed a key role for inhibitory Fc gamma receptors class IIb (FcγRIIb) as negative modulators of innate and adaptive immune responses. Acquired and genetic factors regulate the expression of FcγRIIb receptors and modify their inhibitory potential. Recent advances have highlighted the importance of FcγRIIb receptors in influencing the development of cancer and autoimmunity. The association of increased FcγRIIb expression with tumor development is believed to operate at effector cell level resulting in inhibition of antitumor cytotoxicity. In autoimmune diseases, FcγRIIb receptors play a major role in controlling the amplitude of antibody- and immune complex-mediated reactions. Generally, FcγRIIb deficiency is associated with increased susceptibility and severity to organ-specific and systemic autoimmunity. This article discusses the proposed mechanisms for FcγRIIb deregulation associated with malignant and autoimmune pathology in animal models and human diseases.