Chronic lymphocytic leukemia (CLL) has a heterogeneous clinical course and outcome. Recent advances in the diagnosis and molecular characterization of CLL permit improved prediction of disease prognosis, which could result in better management. We review the biology and diagnosis of CLL and the role of analysis of immunoglobulin heavy-chain variable region mutation status, molecular cytogenetics (interphase fluorescence in situ hybridization), and the expression of CD38 and ZAP-70 in the evaluation and management of patients with CLL.