Therapeutic options for chronic lymphocytic leukemia (CLL) have been limited, with low complete response rates (CR) and no treatments demonstrating a survival advantage. The recent introduction of the monoclonal antibodies rituximab and alemtuzumab into clinical trials for patients with CLL has generated promising results. Rituximab targets the CD20 antigen and demonstrates varied single-agent activity that is highly dependent upon the dosing schedule and treatment status of the patient. More importantly, when rituximab is combined with fludarabine or fludarabine and cyclophosphamide, a high frequency of CR and prolonged progression-free survival are observed without an appreciable increase in significant toxicity. Alemtuzumab targets the more ubiquitously expressed CD52 antigen and is therefore associated with a higher frequency of toxicity, particularly immunosuppression, but has appreciable activity in fludarabine refractory CLL. Additionally, alemtuzumab is effective against CLL clones that have p53 mutations or deletions. Future efforts in developing combination strategies with rituximab, alemtuzumab, and potentially other new antibodies offer great promise for the future treatment of CLL.