A unique property of monoclonal antibodies, and a principal reason for their success as cancer therapeutics, is their ability to engage the immune system. A growing set of data supporting the relevance of Fc-mediated effector functions to anti-tumor efficacy has motivated efforts to enhance the interactions between antibodies and Fc receptors expressed on immune cells. Although current approaches have considerable promise for improved clinical performance, the immunobiology of tumors, antibodies, and Fc receptors continues to evolve. In this review we discuss what is known and what is not known about the interactions between therapeutic antibodies and the immune system, with the goal being progress toward clear target profiles for effector engineering efforts.