Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation/expansion of a clonal population of small mature B lymphocytes in blood, bone marrow, and lymphoid organs. Although initial genetic events are considered primarily responsible for the first step(s) of neoplastic transformation, the development and progression of the CLL clone are thought to be affected by various micro-environmental signals that regulate proliferation and survival of malignant B cells. In the present review, we focus on specific interactions of CLL cells with the microenvironmental component, as they occur through the usage by CLL cells of specific molecular structures whose expression has been associated with prognosis, including: i) interactions of CLL cells via the surface BCR and dependent on specific molecular features of the BCR itself and/or the presence of the BCR-associated molecule ZAP- 70; ii) non-BCR-dependent proliferative and/or pro-survival interactions of CLL cells by CD49d and CD38. An overview of the putative drugs that could be employed to target specific molecules involved in CLL cells/tumor microenvironment interactions is also proposed in the closing chapter of the review.