To review risk stratification strategies used in chronic lymphocytic leukemia at diagnosis to predict aggressiveness of disease and, at time of treatment, to predict duration of response. Several new prognostic factors can better assist clinicians in predicting the aggressiveness of chronic lymphocytic leukemia at diagnosis and the likelihood of maintaining a prolonged remission with treatment. This article reviews older prognostic factors such as beta2-microglobulin and thymidine kinase activity that have been partially validated by recently completed large studies. New prognostic factors such as interphase cytogenetics, immunoglobulin heavy-chain gene mutational analysis, and relevant secondary surrogate markers of immunoglobulin heavy-chain gene, including methylation of the zeta-associated protein gene, lipoprotein lipase overexpression, telomere length, and telomerase activity are reviewed. Some prognostic factors (interphase cytogenetics) but not others (immunoglobulin heavy-chain gene mutational status, zeta-associated protein expression) predict the duration of response to fludarabine-based combination strategies. Recent advances in risk stratification provide clinicians with tools to better predict outcome of chronic lymphocytic leukemia at the time of treatment and response to treatment at the time of developing symptomatic disease.