Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western world. It is characterized by a highly variable clinical course, which is associated with significant clonal dynamics of the leukemic cell population over time. The expansion of subclones carrying various somatic gene variants, many of which are non-recurrent, influences disease progression and treatment response. Our aim was to describe the principles of clonal evolution in CLL concerning specific treatment regimens and different disease stages. We focused particularly on factors affecting the development of subclones with mutations in the TP53 gene, which is the most significant predictive and prognostic marker in CLL. Defects in this gene lead to chemoresistance in patients.