Different pathogenetic mechanisms lead to the accumulation and dissemination of malignant B-cells in lymphoid malignancies. Chronic lymphoproliferative disorders are characterized by defects in the induction of apoptosis and by relevant interactions with the microenvironment. Chronic Lymphocytic Leukaemia (CLL), the most frequent adult leukaemia in the western world, provides an interesting model to investigate the role of microenvironment and especially of antigen stimulation whose role is central in several chronic B-cell tumors. Our aim is to molecularly characterize the natural history of CLL by probing the factors important for its pathogenesis and progression. It is a translational research centered upon the concept that deciphering the biology of CLL may pave the way to new modalities of treatment applicable also to other indolent B-cell malignancies.