Clinical activity of anti-CD20 monoclonal antibodies both in the unlabeled (rituximab [Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA]) and radiolabeled forms, as well as radioimmunoconjugates targeting other antigens, has resulted in the exploration of alternative targets for immunotherapeutic strategies in lymphoma. We report on the rationale for and initial efforts in the development of two unlabeled, humanized monoclonal antibodies directed against molecules commonly expressed in B-cell malignancies. hLL2 (epratuzumab; Immunomedics, Inc, Morris Plains, NJ) binds to the CD22 antigen, while Hu1D10 (apolizumab; Protein Design Labs, Inc, Fremont, CA) reacts with a polymorphism on the HLA-DR beta chain. Preclinical studies and early clinical evaluations suggest that these agents have a potential role as novel therapeutic targets for lymphoma with acceptable toxicity profiles. Further efforts will explore optimal clinical settings for their use, as well as define treatment regimens either as single agents or in combination with chemotherapy or other biologics.