Introduction: The Fc receptors (FcRs) and their interactions with immunoglobulin and innate immune opsonins, such as C-reactive protein, are key players in humoral and cellular immune responses. As the effector mechanism for some therapeutic monoclonal antibodies, and often a contributor to the pathogenesis and progression of autoimmunity, FcRs are promising targets for treating autoimmune diseases. Areas covered: This review discusses the nature of different FcRs and the various mechanisms of their involvement in initiating and modulating immunocyte functions and their biological consequences. It describes a range of current strategies in targeting FcRs and manipulating their interaction with specific ligands, while presenting the pros and cons of these approaches. This review also discusses potential new strategies including regulation of FcR expression and receptor crosstalk. Expert opinion: FcRs are appealing targets in the treatment of inflammatory autoimmune diseases. However, there are still knowledge limitations and technical challenges, the most important being a better understanding of the individual roles of each of the FcRs and enhancement of the specificity in targeting particular cell types and specific FcRs. © 2014 Informa UK, Ltd.