Monoclonal antibodies can mediate antitumor activity by multiple mechanisms. They can bind directly to tumor receptors resulting in tumor cell death, or can bind to soluble growth factors, angiogenic factors, or their cognate receptors blocking signals required for tumor cell growth or survival. Monoclonal antibodies, upon binding to tumor cell, can also engage the host's immune system to mediate immune-mediated destruction of the tumor. The Fc portion of the antibody is essential in engaging the host immune system by fixing complement resulting in complement-mediated cytotoxicity (CDC) of the tumor, or by engaging Fc receptors for IgG (FcγR) expressed by leukocytes leading to antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) of tumor cells. Antibodies whose Fc portion preferentially engage activating FcγRs have shown greater inhibition of tumor growth and metastasis. Monoclonal antibodies can also stimulate the immune system by binding to targets expressed on immune cells. These antibodies may stimulate antitumor immunity by antagonizing a negative regulatory signal, agonizing a costimulatory signal, or depleting immune cells that are inhibitory. The importance of Fc:FcγR interactions in antitumor therapy for each of these mechanisms have been demonstrated in both mouse models and clinical trials and will be the focus of this chapter.