Antibodies are the key effector molecules of the humoral immune system providing long-term protective immunity against a wide range of pathogens and regulating immune responses. Traditionally, antibody-mediated protection against microbes was thought to be mainly a result of neutralizing Fab-antigen interaction; however, an increasing number of studies show the importance of proper FcR engagement for the protective capacity of antimicrobial antibodies. In this chapter, we review FcR-mediated effector functions contributing to antimicrobial protection in a direct and indirect manner. Furthermore, we highlight recent findings about the important role of Fc-FcR interactions for antimicrobial protection in vivo and provide examples demonstrating the crucial role of proper FcR engagement for antibody-mediated protection against viruses, bacteria, fungi, and parasites.