The effective and practical use of mAbs in cancer therapy became a reality with the development of the chimeric anti-CD20 mAb, rituximab. Several additional mAbs have since been approved for clinical use. Despite these successes, the mechanisms by which mAbs mediate antitumor activity are still unclear. Preclinical studies indicate complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) both can contribute to mAb-induced tumor cell lysis. However, evidence related to the relative clinical importance of each mechanism, and whether they are synergistic or antagonistic, is conflicting. New ways to enhance both CDC and ADCC are being developed in attempt to develop a more effective anticancer mAb. Continued research on the mechanisms of mAb therapy will be necessary if we are to take optimal advantage of the current mAbs and develop more effective mAbs in the future.