Chemotherapeutic approaches during the last decade have failed to result in major advances in the outcome of patients with chronic lymphocytic leukemia (CLL). The recent availability of an increasing number of active monoclonal antibodies, immunotoxins, and radioimmunoconjugates (RICs) has stimulated considerable interest in clinical research in CLL. Alemtuzumab was the first antibody approved for CLL on the basis of responses in one third of patients with advanced disease. However, infusion reactions and immunosuppression with opportunistic infections present a challenge that may be overcome with altered schedules and routes of administration. Rituximab has limited activity as a single agent in patients relapsed or refractory after prior chemotherapy; however, response rates seem to be higher in previously untreated patients. More importantly, combinations with chemotherapy drugs such as fludarabine are showing promise in early trials. Newer antibodies in development as single agents and in combinations include apolizumab (Hu1D10), a humanized antibody against an epitope of HLA-DR, and IDEC-152, a primatized anti-CD23 antibody. BL22, an immunotoxin with impressive activity in hairy cell leukemia, is in phase II trials in CLL as well. The safe use of RICs is complicated by the elevated peripheral blood B-cell count, and the extent of bone marrow involvement in CLL; studies will explore the use of agents to eliminate malignant cells from the bone marrow before RIC therapy. It is hoped that the rational development of combinations of the various promising antibodies with chemotherapy and each other will lead to more effective approaches for patients with CLL.