B-cell chronic lymphocytic leukemia (CLL) is a clonal hematopoietic disorder characterized by proliferation and accumulation of small lymphocytes. It is the most common form of leukemia in North America and Europe. The management of CLL is determined by the stage and activity of the disease. Several randomized studies indicate that cytotoxic therapy based on alkylating agents in the indolent phase of disease, does not prolong the survival time of CLL patients. Chlorambucil, with or without steroids, has been for many years the drug of choice in previously untreated patients with this leukemia. Alternative treatment approaches, including new purine nucleoside analogs (PNA), such as fludarabine and 2-chlorodeoxyadenosine (cladribine) have also shown activity in CLL. The randomized studies have indicated a higher overall response, complete remission rates and longer response duration in patients treated initially with PNA than with chlorambucil or cyclophosphamide based combination regimens. These agents alone or in combinations, seem to be the treatment of choice for patients failing standard therapies. The monoclonal antibodies directed against CD52 antigen (alemtuzumab, Campath-1H) and CD20 antigen (rituximab) demonstrate also significant activity in CLL patients. These agents have significant single-agent activity, distinct mechanism of action and generally, favorable toxicity profiles. Both antibodies achieved the most promising results in the treatment of patients with relapsed or refractory CLL. More recently the effect of alemtuzumab in previously untreated patients has been also investigated and results are very encouraging. A multicenter prospective randomized study comparing alemtuzumab and chlorambucil as first line therapies are ongoing and preliminary results show acceptable toxicity profile of monoclonal antibody.