Engineered antibody therapeutics have provided new treatment options in cancer. Genetic evidence in man and in the mouse suggests that Fc receptor (FcR) engagement contributes mechanistically to the therapeutic activity of naked antibodies. Preferential activation of activating FcRs and limited engagement of inhibitory FcRs enhance tumor responses in mouse models. Thus, engineered Fc domains with favorable affinities for specific FcR types may prove to be clinically superior.