Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world and is due to the accumulation of mature B lymphocytes in the peripheral blood, bone marrow and secondary lymphoid organs. The leukemic cells show a distinct phenotype, which is essential to reach the correct diagnosis. Despite the phenotypic homogeneity, the clinical outcome may be significantly different. Some patients have an indolent leukemia, with long survival while others experience an aggressive disease, with early and frequent need of treatment. At present, no chemotherapeutic regimens can be considered curative and all patients will die with (or because of) their disease. In recent years, research on CLL has led to important discoveries that help defining patients' prognosis at the moment of diagnosis. These prognostic factors, which are derived from the biological features of the leukemic lymphocytes, are now rapidly moved into the clinical arena. They are used to stratify patients in selected clinical trials to assess the value of early and more modern treatments, which are becoming available to hematologists.