The absence of mutations in the IgV genes, together with the presence of ZAP-70 and CD38, are the most reliable negative prognostic markers for chronic lymphocytic leukemia (CLL) patients. Several lines of evidence indicate that CD38 may be not only a diagnostic marker but also a key element in the pathogenetic network in CLL. First, CD38 is a receptor that induces proliferation and increases survival of CLL cells. Second, CD38 signals start upon interaction with the CD31 ligand expressed by stromal and nurse-like cells. Third, CD38/CD31 contacts up-regulate CD100, a semaphorin involved in sustaining CLL growth. Fourth, evidence that nurselike cells express high levels of CD31 and plexin-B1, the high-affinity ligand for CD100, offers indirect confirmation for this model of receptor cross-talk. Elements of variation in the clinical course of CD38(+) CLL patients include (1) potential intersection with ZAP-70, a kinase involved in the CD38 signaling pathway in T and natural killer (NK) cells, and (2) the effects of genetic polymorphisms of the receptors involved, at least of CD38 and CD31. Consequently, CD38 together with ZAP-70 appear to be the key elements of a coreceptor pathway that may sustain the signals mediated by the B-cell receptor and potentially by chemokines and their receptors. This would result in acquisition of increased survival potential, providing clues to the poorer prognosis of CD38(+) patients.