Human CD38, an ecto-enzyme and a receptor, performs as an independent negative prognostic marker for patients with chronic lymphocytic leukemia (CLL), a hematological malignancy characterized by the accumulation of a population of mature B lymphocytes expressing CD5. Patients with a CD38⁺ CLL clone display a more aggressive form of the disease with earlier treatment requirements and ultimately shorter overall survival than patients with a CD38⁻ clone. Several lines of evidence indicate that CD38 is not only a diagnostic marker but also a key element in the molecular network regulating disease maintenance and progression. First, CD38 is a receptor that induces proliferation and increases survival of CLL cells. Second, CD38 signals facilitate access of CLL cells to growth-favorable districts. This is achieved by enhancing i) chemotaxis towards CXCL12, ii) integrin-mediated adhesion and iii) matrix metalloprotease synthesis and secretion. Third, blocking monoclonal antibodies targeting CD38 impair CLL homing to spleen and bone marrow in xenograft models. These functions appear to be modulated by frontal interactions with CD31 as well as by lateral associations on the CLL membrane to form a large supramolecular complex similar to the invadosomes of epithelial cells. Our understanding has evolved from considering CD38 as a marker of unfavorable prognosis to recognizing its function as a disease modifier. Studies in the next few years will likely determine whether the molecule can also serve as a target for new therapies, using monoclonal antibodies, inhibitors of the enzymatic activity or both.