The ability of monoclonal antibodies (mAbs) specific for CD40, a member of the tumor necrosis factor receptor (TNFR) family found on antigen-presenting cells (APCs), to induce antitumor immunity has until now been disappointing. Li and Ravetch show that, counterintuitively, mutations in the Fc regions of CD40-binding mAbs that increase mAb affinity for the APC Fcγ receptor IIb (FcγRIIb)—a receptor previously thought to downregulate activity—stimulate antitumor immunity by activating cytotoxic T cells. Therapeutic benefits are reflected both by reduced tumor growth and prolonged survival relative to treatment with conventional CD40 mAbs. It remains to be established whether antibodies mutated in their Fc regions to promote FcγRIIb engagement couple CD40 and FcγRIIb molecules on the same or different APCs, whether FcγRIIb activation can enhance antibody-dependent cellular cytotoxicity triggered by mAbs specific for other TNFR homologs, and what signaling events account for the somewhat unexpected adjuvant effects of engaging inhibitory, but not activating, Fcγ receptors. (Science 333, 1030–1034, 2011)