Chronic lymphocytic leukemia is the most common leukemia in Western countries affecting particularly elderly adults. Despite the constantly improving therapy options, chronic lymphocytic leukemia is still an incurable disease owing to considerable clinical and biological heterogeneity. Pathogenesis of chronic lymphocytic leukemia is not fully understood; however, aberrant antigenic stimulation, apoptosis deregulation and microenvironmental interactions play a crucial role in disease development. The most important molecular prognostic markers with clinical relevance include mutation status of heavy-chain immunoglobulin genes (IGHV), presence of cytogenetic aberrations and TP53 and ATM gene mutations. Recent implementation of next generation sequencing technologies has enabled more accurate analysis of both well-established and novel potential prognostic markers. The most relevant candidates are mutations in SF3B1, NOTCH1 and BIRC3 genes, which are now intensively studied with respect to their clinical importance. The other examined molecular mechanisms of chronic lympho cytic leukemia pathogenesis include deregulation of B-cell receptor signalization and abnormal regulation of gene expression by microRNA. The precise characterization of molecular abnormalities improves the risk stratification of chronic lymphocytic leukemia patients, which could possibly benefit from new treatment approaches.