Leukocyte membrane receptors for the Fc portion of Igs (FcRs) link antigen recognition by antibodies to effector functions involved in immune phenomena, from pathogen elimination to autoimmunity. Moreover, they also signal for the synthesis and secretion of cytokines and chemokines, thus having a role in immune homeostasis. Even though the structural and functional similarities between FcRs and the clonotypic antigen receptors of lymphocytes (the T-cell receptor and B-cell receptor) are well established, participation of regulatory membrane molecules in leukocyte activation by FcRs has rarely been considered. Here, we summarize evidence demonstrating that FcR-mediated signaling could be modulated by other membrane molecules (signal regulators), and propose that comprehension of this phenomenon is essential for understanding the functions of FcRs, knowledge of which could then be used for therapeutic interventions.