The introduction of the monoclonal antibodies rituximab (anti-CD20) and alemtuzumab (anti-CD52) has revolutionized the treatment of chronic lymphocytic leukemia (CLL). Both antibodies were first studied as single agents in relapsed CLL, but rituximab is increasingly used in combination chemoimmunotherapy regimens in previously untreated patients. Phase II studies demonstrated that the addition of rituximab to fludarabine-based chemotherapy improves complete response (CR) rates and prolongs progression-free survival (PFS), but a long-term survival benefit has not been shown. Alemtuzumab is less commonly used, due to the greater likelihood of infusion toxicity, as well as hematologic and immune toxicities. Subcutaneous (SC) administration significantly reduces infusion toxicity, but hematologic and infectious complications, most notably cytomegalovirus (CMV) reactivation, still occur with SC dosing. Alemtuzumab's unique clinical properties include its clinical activity in relapsed CLL patients with del(17p13) and its ability to eradicate minimal residual disease (MRD) in bone marrow. Its use as consolidation therapy to eradicate MRD after nucleoside analog therapy is under active study. Several investigational monoclonal antibodies are in preclinical or clinical studies, most notably lumiliximab (anti-CD23) and ofatumumab (HuMax CD20), and are briefly discussed in this review.