Interactions between malignant B lymphocytes and the tissue microenvironment 
play a major role in the pathogenesis of chronic lymphocytic leukemia (CLL) and 
other B-cell malignancies. The coexistence and coevolution of CLL cells with 
their tissue neighbors provided the basis for discovery of critical cellular and 
molecular drivers of the disease and identification of new therapeutic targets. 
Bone marrow stromal cells (BMSC), monocyte-derived nurselike cells (NLC), and T 
cells are key players in the CLL microenvironment, which activate and protect 
CLL cells within the tissues. CLL surface molecules, such as the B-cell antigen 
receptor (BCR), chemokine receptors, adhesion molecules, and TNF receptor 
superfamily members (e.g., CD40, BCMA, and BAFF-R) engage in cross-talk with 
respective tissue ligands. This cross-talk results in survival and expansion of 
the CLL clone, and protects CLL cells from conventional cytotoxic drugs. 
Inhibiting these pathways represents an alternative therapeutic strategy to more 
conventional chemoimmunotherapy. Here, we review central components of the CLL 
microenvironment, with a particular emphasis on BCR signaling, and we summarize 
the most relevant clinical advances with inhibitors that target the 
BCR-associated spleen tyrosine kinase/SYK (fostamatinib), Bruton's tyrosine 
kinase/BTK (ibrutinib), and PI3Kδ (idelalisib).