In spite of being the most prevalent adult leukemia in Western countries, the molecular mechanisms driving the establishment and progression of chronic lymphocytic leukemia (CLL) remain largely unknown. In recent years, the use of next-generation sequencing techniques has uncovered new and, in some cases, unexpected driver genes with prognostic and therapeutic value. The mutational landscape of CLL is characterized by high-genetic and epigenetic heterogeneity, low mutation recurrence and a long tail of cases with undefined driver genes. On the other hand, the use of deep sequencing has also revealed high intra-tumor heterogeneity and provided a detailed picture of clonal evolution processes. This phenomenon, in which aberrant DNA methylation can also participate, appears to be tightly associated to poor outcomes and chemo-refractoriness, thus providing a new subject for therapeutic intervention. Hence, and having in mind the limitations derived from the CLL complexity thus described, the application of massively parallel sequencing studies has unveiled a wealth of information that is expected to substantially improve patient staging schemes and CLL clinical management.