Chronic lymphocytic leukemia (CLL) is one of the most commonly diagnosed leukemias managed by practicing hematologists. For many years patients with CLL have been viewed as similar, with a long natural history and only marginally effective therapies that rarely yielded complete responses. Recently, several important observations related to the biologic significance of V(H) mutational status and associated ZAP-70 overexpression, disrupted p53 function, and chromosomal aberrations have led to the ability to identify patients at high risk for early disease progression and inferior survival. Concurrent with these investigations, several treatments including the nucleoside analogues, monoclonal antibodies rituximab and alemtuzumab have been introduced. Combination of these therapies in clinical trials has led to high complete and overall response rates when applied as initial therapy for symptomatic CLL. Thus, the complexity of initial risk stratification of CLL and treatment has increased significantly. Furthermore, when these initial therapies do not work, approach of the CLL patient with fludarabine-refractory disease can be quite challenging. This session will describe the natural history of a CLL patient with emphasis on important decision junctures at different time points in the disease. In Section I, Dr. Stephan Stilgenbauer focuses on the discussion that occurs with CLL patients at their initial evaluation. This includes a review of the diagnostic criteria for CLL and prognostic factors utilized to predict the natural history of the disease. The later discussion of risk stratification focuses on molecular and genomic aberrations that predict rapid progression, poor response to therapy, and inferior survival. Ongoing and future efforts examining early intervention strategies in high risk CLL are reviewed. In Section II, Drs. Ian Flinn and Jesus G. Berdeja focus on the discussion of CLL patients when symptomatic disease has developed. This includes an updated review of monotherapy trials with nucleoside analogs and recent trials that have combined these with monoclonal antibodies and/or alternative chemotherapy agents. Appropriate application of more aggressive therapies such as autologous and allogeneic immunotherapy and less aggressive treatments for appropriate CLL patient candidates are discussed. In Section III, Dr. John Byrd focuses on the discussion that occurs with CLL patients whose disease is refractory to fludarabine. The application of genetic risk stratification in choosing therapy for this subset of patients is reviewed. Available data with conventional combination based therapies and monoclonal antibodies are discussed. Finally, alternative promising investigational therapies including new antibodies, kinase inhibitors (CDK, PDK1/AKT, PKC) and alternative targeted therapies (DNA methyltransferase inhibitors, histone deacetylase inhibitors, etc.) are reviewed with an emphasis on the most promising agents for this patient population.