In chronic lymphocytic leukemia (CLL), genetic analyses by fluorescence in situ hybridization (FISH) and DNA sequencing have greatly improved our understanding of pathogenic events and prognostic markers. On the one hand, there are genomic aberrations, which are detected in over 80% of CLL cases, and genes potentially involved in 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 the 11q deletion that is associated with marked lymphadenopathy and rapid disease progression, while the 17p deletion predicts treatment failure with alkylating agents as well as fludarabine and short survival times. On the other hand, there is the mutation status of the VH genes that allows the separation of patients into 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). Most importantly, the VH mutation status and genomic abnormalities have been shown to be of independent prognostic value in multivariate analysis, appear to allow outcome predication irrespective of the clinical stage, and may therefore allow a risk assessment of individual patients early in the course of the disease.