Antibodies targeting T-cell inhibitory pathways, such as CTLA-4 and PD-1/PD-L1, are emerging as an important class of cancer therapeutics, and a next generation of immunomodulatory therapies targeting alternative inhibitory (e.g. TIM-3, LAG-3, B7-H4, B7-H3, VISTA, A2aR), as well as co-stimulatory (e.g. CD27, OX40, GITR, CD137), pathways are poised to join them. Most of these immunomodulatory antibodies are of IgG isotypes that have low, or no, binding to the Fc gamma receptors (FcγRs) that trigger cell-mediated cytotoxic effector functions such as antibody dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). These isotypes were selected to minimise the risk of depleting the T cells upon which such antibodies depend for their mechanism of action. However, recent preclinical data highlight a potential role for FcγR engagement in the activity of such antibodies. Here we review the biology of the FcγRs and IgG isotypes in both humans and mice, detail the potential roles that FcγR interactions can play in the activity of monoclonal antibodies in general, and of immunomodulatory antibodies in particular, and discuss how preclinical studies on these interactions might be best interpreted and translated to a human setting.