The newer purine nucleoside analogues (PNA), fludarabine (FAMP) and cladribine (2-chlorodeoxyadenosine, 2-CdA) have been synthesized recently and introduced into the treatment of chronic lymphocytic leukemia (CLL). The results of large phase II studies indicate that FAMP and 2-CdA are similarly active in CLL. Unfortunately, no prospective randomized study comparing the results of the treatment of CLL patients with FAMP and 2-CdA has been published so far. Significantly higher overall response (OR) and complete remission (CR) in patients treated initially with PNA than with chlorambucil or cyclophosphamide based combination regimens has been recently confirmed in five prospective multicentre randomized trials. These studies have also shown longer response duration in patients treated with PNA than with conventional chemotherapy. Overall survival progression free and events free survival were similar in patients treated with PNA and with chlorambucil or other alkylating agent based regimens. However, the majority of randomized trials were designed as cross over studies and most patients, treated with conventional chemotherapy were given PNA when refractory or in early relapse, which may influence the survival time. The results of a randomized study have shown a higher incidence of neutropenia and infections in patients treated with PNA than with chlorambucil. However. the frequency of autoimmune hemolytic anemia, pure red cell aplasia, secondary neoplasms and Richter's syndrome seems to be similar in patients treated with PNA and standard alkylating agents based chemotherapy. In conclusion, alkylating agents still have an important place in the routine management of the majority of CLL patients. They are in general safe, given on an out patients basis and significantly cheaper than PNA. PNA should be routinely used as second line treatment, and possibly as first line therapy in younger patients, who are candidates for potentially curative treatment such as stem cell transplantation and/or monoclonal antibodies.