Chronic lymphocytic leukemia (CLL) follows an extremely variable clinical course with survival ranging from months to decades. Available treatments can often induce remissions, but eventually all patients relapse. Recently, there has been major progress in the identification of molecular and cellular markers that may predict the tendency for disease progression in patients with CLL. Genomic aberrations, the mutational profile of IgVH genes and its surrogate marker ZAP-70 expression, and serum markers like B2-microglobulin (beta2-MG) and thymidine kinase (TK) provide prognostic information for individual patients independently of clinical disease characteristics. These molecular markers are about to enter the stage of risk stratification for individual patients in clinical trials.