Molecular genetic methods such as fluorescence in situ hybridization and DNA sequencing have greatly improved our understanding of pathogenic events and prognostic markers in chronic lymphocytic leukemia (CLL). There are genomic aberrations detected in over 80% of CLL cases, and genes potentially involved in the pathogenesis were identified with ATM in a subset of cases with 11q deletion and p53 in cases with 17p13 deletion. Genetic subgroups with distinct clinical features have been identified, such as 11q deletion, which is associated with marked lymphadenopathy and rapid disease progression, whereas 17p deletion predicts for treatment failure with alkylating agents, fludarabine, and short survival times. There is mutation status of the VH genes that allows the separation into patients with long (mutated VH) or short (unmutated VH) survival times. V-gene usage, VDJ structure, and gene expression differences in the two subgroups allow insights into differential pathogenic mechanisms and provide further prognostic information (V3-21 usage, ZAP-70 expression). The VH mutation status and genomic abnormalities have been shown to be of independent prognostic value in multivariate analysis, seem to allow outcome predication irrespective of the clinical stage, and may therefore allow a risk assessment for individual patients early in the course of their disease.