CD38, an adenine dinucleotide phosphate (ADP) ribose cyclase and a cyclic ADP ribose hydrolase, is widely expressed on the surface of multiple myeloma (MM) cells. It is known to play a pivotal role in the downstream pathways that mediate MM cell growth, signal transduction, and adhesion. The clinical use of CD38 monoclonal antibodies (MoAbs), such as daratumumab, either as monotherapy or in combination with other anti-MM agents, has produced impressive results in patients who have failed standard MM therapy. CD38 MoAbs exhibit several cytotoxic mechanisms on MM cells. In addition to the classical effector mechanisms associated with antibody therapy, CD38 MoAbs induce MM apoptosis and clonal T-cell expansion. Here, we summarize the results of some pivotal clinical studies using a human CD38 MoAb, daratumumab, in patients with MM, discuss the anti-MM effector mechanisms induced by CD38 MoAbs, and review the potential tumor antigens that may be suitable targets for immunotherapy of MM. Finally, we present a paradigm of immunotherapy for MM patients using CD38 MoAbs followed by GM-CSF and an immune checkpoint inhibitor in patients who have undergone high dose chemotherapy and autologous stem cell transplant. CD38 MoAbs have emerged as a novel and ultimately very promising immunotherapeutic agent for MM because of its ability to induce MM cytotoxicity through both arms of the adaptive immune responses.