Chronic lymphocytic leukemia (CLL) has been considered as an accumulative disease deriving from defects in apoptosis, but recent studies showed that CLL is a dynamic process in which monoclonal B cells proliferate within pseudofollicular proliferation centers. Microenvironmental interactions are essential for the survival and prolifera‐ tion of CLL cells. The cell traffic between blood and secondary lymphoid tissues is controlled by tissue-specific chemokines and their specific receptors on B lympho‐ cytes. Interstitial cell migration and adhesion events, predisposed by activational stimuli, determine CLL cell localization. Stimulation through the B cell receptor plays an important role in the expansion of the malignant clone in CLL. B cell receptors become activated either in an antigen-dependent or in an antigen-independent fashion in the secondary lymphatic tissues. However, low expression of the BCR correlates with reduced induction of protein tyrosine kinase activity and defective intracellular calcium mobilization and tyrosine phosphorylation. In contrast to normal B cells, leukemic cells are poor antigen presenting cells. This is due to the fact that leukemic cells have a reduced expression of costimulatory molecules and defects in the formation of immunological synapse with T cells. Increased surface expression of the costimulatory molecules on CLL cells correlates with their proliferation. At present, conventional treatments are not directed to interactions between CLL cells and their microenvironment, which is probably one of the reasons why, despite the significant progress in treatment, the disease still remains incurable. In this regard, identifying key biomarkers of intercellular interactions of neoplastic CLL population in comparison with clinical laboratory abnormalities in CLL enable clarification of essential processes in the development of the disease, and can be the basis for © 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. stratifying patient groups in order to optimize therapeutic approaches, which will make them relevant and promising.