CLL is characterized by a dynamic balance between cells proliferating in the lymphoid organs and circulating cells resisting programmed cell death. Regulating this equilibrium entails complex interactions between tumor and host, modulated by a set of surface molecules expressed by the CLL cell according to environmental conditions. The result is a constantly shifting pattern of resistance, apoptosis and proliferation. The CD38 surface molecule is an independent negative prognostic factor expressed by approximately one-third of CLL patients. Our view is that CD38 is crucial to tumor–host communication and that its signals are detrimental to clinical outcome. CD38⁺ CLL cells can proliferate in vitro in the presence of anti-CD38 mAbs and IL-2 and are more sensitive to the effects of the CXCL12 chemokine. Blockage of CD38 signals impairs CLL cell movement from blood to lymphoid organs, as confirmed using animal models. One model to be explored considers CD38 a key component of the CLL invadosome, a still hypothetical membrane domain containing adhesion molecules, chemokine receptors and matrix metalloproteases. Some components of the invadosome are genetically polymorphic, explaining heterogeneity in functional response. The CD38 gene shows genetic differences in the promoter region, some of which represent an independent risk for Richter transformation. In addition to driving the clinical outcome of the disease, CD38 is thus an excellent candidate therapeutic target for a significant subset of CLL patients.