Introduction CD38 is expressed by some cells of hematological malignancies and tumor-related immunosuppressive cells, including regulatory T cells, regulatory B cells, and myeloid-derived suppressor cells. CD38 is an effective target in some hematological malignancies such as multiple myeloma (MM). Daratumumab (Dara), a CD38-targeting antibody, can eliminate CD38(high)immune suppressor cells and is regarded as a standard therapy for MM because of its outstanding clinical efficacy. Other CD38 monospecific antibodies, such as isatuximab, MOR202, and TAK079, showed promising effects in clinical trials. Area covered This review examines the expression, function, and targeting of CD38 in MM and its potential to deplete immunosuppressive cells in solid cancers. We summarize the distribution and biological function of CD38 and discuss the application of anti-CD38 drugs in hematological malignancies. We also analyz the role of CD38(+)immune cells in the tumor microenvironment to encourage additional investigations that target CD38 in solid cancers. PubMed and ClinicalTrials were searched to identify relevant literature from the database inception to 30 April 2020. Expert opinion There is convincing evidence that CD38-targeted immunotherapeutics reduce CD38(+)immune suppressor cells. This result suggests that CD38 can be exploited to treat solid tumors by regulating the immunosuppressive microenvironment.