Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature monoclonal B cells in peripheral blood, bone marrow, spleen, and lymph nodes. The trafficking, survival, and proliferation of CLL cells is tightly regulated by the surrounding tissue microenvironment and is mediated by antigenic stimulation, close interaction with various accessory cells and exposure to different cytokines, chemokines, and extracellular matrix components. In the last decade there have been major advances in the understanding of the reciprocal interactions between CLL cells and the various microenvironmental compartments. This article discusses the role of the microenvironment in the context of efforts to develop novel therapeutics that target the biology of CLL.