The fist in class CD38-targeting antibody, daratumumab, is currently approved as single agent and in combination with standards of care for the treatment of relapsed and refractory multiple myeloma. Based on the high activity and favorable toxicity profile of daratumumab, other CD38 antibodies, such as isatuximab, MOR202, and TAK-079, are being evaluated in MM and other malignancies. The CD38-targeting antibodies have classic Fc-dependent immune effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). These mechanisms of action are dependent on CD38 expression on the tumor cells. There is increasing evidence that CD38 antibodies also improve host-anti-tumor immune response by eliminating CD38-positive immune suppressor cells, including regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells. Indeed, daratumumab treatment results in a marked increase in T cell numbers and activity. CD38-targeting antibodies probably also reduce adenosine production in the bone marrow microenvironment, which may contribute to improved T cell activity. Preclinical and clinical studies have demonstrated that CD38-targeting antibodies have synergistic activity with several other anti-cancer drugs, including various agents with immune stimulating activity, such as lenalidomide and pomalidomide, as well as PD1/PD-L1 inhibitors.