Chronic lymphocytic leukemia (CLL) is truly a heterogeneous disease, in which individual outcomes range from no need for therapeutic intervention to very aggressive, nonresponding disease. The ability to develop clear, sound prognostic information that permits reliable counsel must be our goal. A combination of easily obtainable, traditional prognostic parameters (bone marrow infiltration patterns, beta-2 microglobulin) along with the clinical Rai stage is still frequently used in the initial risk stratification of patients with CLL. However, novel parameters such as defects detectable on fluorescence in situ hybridization (FISH), expression levels of CD38 and ZAP-70, and immunoglobulin heavy-chain variable region status can add significant prognostic information about a given patient with CLL. How to incorporate these newer tests within the context of the more traditional parameters for a patient with a new diagnosis is the focus of significant continuing research. The outcome of this research has implications for predicting clinical progression rates and the response and duration of response to therapy, as well as for highlighting high-risk patients who will need earlier or more specific treatment approaches.