Chronic lymphocytic leukemia (CLL) is characterized by extreme genomic heterogeneity. Numerous recurrent genetic abnormalities are associated with dismal clinical outcome in patients treated with chemo(immuno)therapy, with aberrations of the TP53 gene being the main genomic abnormalities that dictate treatment choice. In the era of novel agents the predictive significance of the genomic aberrations is highly challenged as the results of the clinical trials performed thus far question the previously established unfavorable impact of genomic aberrations, even that of the TP53 gene. The prognostic and predictive value of the most common genomic abnormalities is discussed in the present review.