The initiating event in CLL is thought to be genetic damage to a class of B lymphocytes that prevents proper functioning of apoptotic pathways. However, disease progression is driven by signals from the proliferation centers in tumor microenvironments where circulating CLL cells originate. Signals that cause CLL cells to proliferate include antigens that activate B-cell receptors (BCRs), Toll-like receptor ligands, chemokines, and cytokines. CLL cells that respond strongly to these microenvironmental signals exhibit more aggressive clinical behavior and resistance to cytotoxic drugs. These observations have motivated the use of signal transduction inhibitors to treat CLL and initial results of targeting kinases in the BCR-signaling cascade, such as Bruton's Tyrosine Kinase (BTK), suggest this strategy is effective and likely to change the treatment paradigm for CLL.