CD38 is a type II transmembrane glycoprotein that is highly expressed in hematological malignancies, including multiple myeloma (MM). Therefore, CD38 is a promising target for antibody immunotherapy. Daratumumab is a human monoclonal antibody with broad-spectrum killing activity. In vitro, daratumumab induces anti-MM effects via complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis. Synergistic activity was demonstrated in vitro in combination with standard MM therapies, including bortezomib and lenalidomide. Protective bone marrow stromal cells did not influence daratumumab-induced CDC and ADCC, suggesting that daratumumab may have activity in the bone marrow microenvironment in vivo. Indeed, significant daratumumab-mediated tumor growth inhibition was shown in MM mouse xenograft models. A phase I/II clinical study is ongoing in patients with relapsed/refractory MM. This review discusses the preclinical pharmacology, pharmacokinetics and preliminary clinical efficacy of daratumumab and its potential in MM therapy.