Antibodies are secreted to recognize and in some cases directly neutralize pathogens. Another important means by which they are essential components of the immune system is through binding to Fc receptors. Effector responses triggered by antibody binding of Fc receptors affect a host of important cellular responses such as phagocytosis, inflammatory cytokine release, antigen presentation, and regulation of humoral responses. A crucial check on this antibody-mediated signal is through the inhibitory receptor, FcgammaRIIB. In this review we discuss how dysregulation of FcgammaRIIB can result in a lowered threshold for autoimmunity in mice and humans. We close with a discussion of the potential for applying these findings to immunotherapy.