Historically, treatment of chronic lymphocytic leukemia (CLL) essentially had been palliative. During the past two decades, effective new therapies for the treatment of CLL have emerged. The advent of fludarabine, a purine analog with activity against chlorambucil-resistant CLL, showed promising results with high response rates in previously untreated patients. These improvements in response and delays in disease progression have not translated into a survival benefit, indicating that chlorambucil may be the preferred first-line therapy when treatment is indicated. Allogeneic hematopoietic stem cell transplantation, by combining the cytoreductive effects of conditioning with a potent graft-versus-tumor effect, is the only treatment modality with the prospect of cure for patients with CLL. However, conventional hematopoietic stem cell transplantation can be offered only to select patients with CLL because of older age and comorbid conditions. Novel methods of transplantation exploiting the graft-versus-leukemia effect while reducing the toxicity of the pretransplant conditioning are promising approaches that may enable more patients to benefit from this therapy. Monoclonal antibodies such as rituximab or alemtuzumab (Campath-1H; llex Pharmaceuticals, San Antonio, TX) are agents with activity in untreated and resistant CLL. Efforts are being focused on combining these monoclonal antibodies with chemotherapy and the development of rationally designed drugs.