For many years, alkylating agents, especially chlorambucil, have been considered the drugs of choice for first-line treatment of progressive and symptomatic chronic lymphocytic leukemia (CLL). More recently, treatment approaches have included purine nucleoside analogs (PNAs), fludarabine or cladribine (2-CdA), and monoclonal antibodies (MoAbs). PNAs are highly active in patients with CLL, previously treated and untreated. Significantly higher overall response and complete response in patients treated initially with fludarabine or 2-CdA than in those treated with chlorambucil- or cyclophosphamide-based combination regimens have been recently confirmed in prospective, randomized trials. However, the median survival times do not differ among the patients treated with PNA and alkylating agents. The MoAbs directed against CD52 antigen (alemtuzumab) and CD20 antigen (rituximab) also demonstrate significant activity in CLL and should be used in patients with disease that is refractory to PNAs. Combination therapies with PNAs and cyclophosphamide, and especially with rituximab, are more active than monotherapy with PNAs in regard to response rate and possible survival. Because most patients are older and there is no survival time advantage for alkylating agents or PNA therapies, we recommend chlorambucil as the first-line treatment, with PNAs for consideration as the second-line therapy. PNAs alone or in combination with cyclophosphamide and rituximab as first-line treatment are an option in younger patients, who may be candidates for consolidation therapy with alemtuzumab and/or stem cell transplantation. Alemtuzumab may be an effective treatment for patients refractory to PNAs. Several biological parameters have been gaining increasing importance to evaluate the prognosis of patients with CLL and define optimal therapeutic strategy. Moreover, novel therapies are being evaluated, especially in patients refractory to PNAs, including those targeting the antiapoptotic bcl-2 family of proteins and receptors, vaccines, and allogenic stem cell transplantation, especially after nonmyeloablative chemotherapy.