The clinical staging systems by Rai and Binet have remained the mainstay for clinical decision-making in patients with chronic lymphocytic leukemia (CLL). However, there is substantial heterogeneity of the disease within the clinical stage groups. In recent years, molecular and cellular markers have helped to predict the prognosis of CLL patients. The mutation status of the variable region of the Ig heavy chain (VH status) and genomic aberrations subdivide CLL into distinct clinical subgroups. Fluorescence in situ hybridization (FISH) can identify genomic aberrations in approximately 80% of CLL cases. Although the FISH technique is used most widely, other approaches (array-CGH, SNP-arrays or CD40 or CpG-stimulated metaphase cytogenetics) show similar results, but assess all chromosomal regions. The most frequent aberrations are deletions in 13q, 11q or 17p, and trisomy 12. Apart from providing insights into the pathogenesis, genomic aberrations identify subgroups of patients with distinct clinical pictures (lymphadenopathy (11q-) or chemotherapy resistance (17p-)). Deletions at 11q and particularly 17p are associated with rapid disease progression or inferior survival and patients with these genetic abnormalities are candidates for clinical trials investigating alternative treatments and stem cell transplantation. Similarly, abnormalities associated with good prognosis may benefit from de-escalation of current treatment approaches.