CD38 is a multifunctional cell surface protein endowed with receptor/enzymatic functions. The protein is generally expressed at low/intermediate levels on hematological tissues and some solid tumors, scoring the highest levels on plasma cells (PC) and PC-derived neoplasia. CD38 was originally described as a receptor expressed by activated cells, mainly T lymphocytes, wherein it also regulates cell adhesion and cooperates in signal transduction mediated by major receptor complexes. Furthermore, CD38 metabolizes extracellular NAD+, generating ADPR and cyclic ADPR. This ecto-enzyme controls extra-cellular nucleotide homeostasis and intra-cellular calcium fluxes, stressing its relevance in multiple physiopathological conditions (infection, tumorigenesis and aging). In clinics, CD38 was adopted as a cell activation marker and in the diagnostic/staging of leukemias. Quantitative surface CD38 expression by multiple myeloma (MM) cells was the basic criterion used for therapeutic application of anti-CD38 monoclonal antibodies (mAbs). Anti-CD38 mAbs-mediated PC depletion in autoimmunity and organ transplants is currently under investigation. This review analyzes different aspects of CD38's role in regulatory cell populations and how these effects are obtained. Characterizing CD38 functional properties may widen the extension of therapeutic applications for anti-CD38 mAbs. The availability of therapeutic mAbs with different effects on CD38 enzymatic functions may be rapidly translated to immunotherapeutic strategies of cell immune defense.