Proteasome inhibitors and immunomodulatory drugs have contributed to the dramatic improvement in survival for patients with myeloma over the past decades. However, the disease typically relapses and new classes of drugs are needed. In 2015, two monoclonal antibodies were approved for the treatment of patients with relapsed multiple myeloma, and immunotherapy has rapidly become indispensable in the management of myeloma patients. Areas covered: Here, the authors discuss the published data regarding the mechanism of action, safety and clinical efficacy of the CD38-targeted monoclonal antibody daratumumab for the treatment of patients with multiple myeloma. Expert opinion: Daratumumab is indicated for myeloma patients who have received at least 3 prior therapies, including bortezomib, lenalidomide and pomalidomide. In 2016, daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone was approved for the treatment of patients with multiple myeloma who have received at least one prior therapy. Daratumumab displays an excellent safety profile. Moderate-grade infusion-related reactions occurring mostly during the first infusion are the main treatment-emergent adverse event. In the context of daratumumab therapy, attention should be paid to interference with blood compatibility testing and response assessment. Daratumumab-based combination therapies are currently under evaluation in relapsed and newly diagnosed patients.