Experimental radioimmunotherapy (RIT) studies in animal models have contributed significantly to the design of clinical RIT protocols, although the results have not always been directly translated. Reviewed in this article are current areas of active research in experimental RIT to increase the therapeutic ratio that are likely to have a significant impact on the design of future clinical studies. Approaches for increasing the therapeutic efficacy of RIT include the development of new targeting molecules (genetically engineered monoclonal antibodies, antibody fragments, single- chain antibodies, diabodies and minibodies, fusion toxins, or peptides); improved labeling chemistry; novel radionuclide use and fractionation; locoregional administration; pretargeting; use of biological response modifiers or gene transfer techniques to increase target receptor expression; bone marrow transplantation; and combined modality therapy with external-beam radiation therapy, chemotherapy, or gene therapy. Further research with these new experimental approaches in preclinical animal models is necessary to contribute to advances in the treatment of cancer patients using radiolabeled antibodies and peptides. Copyright (C) 2000 by W.B. Saunders Company.