The interleukin (IL)-2 receptor has proved an attractive target for T cell-directed therapies. Agents including monoclonal antibodies, single-chain antibody immunoconjugates, radioimmunoconjugates, and, most recently, ligand fusion toxins have demonstrated activity in vitro and in clinical trials in both hematologic malignancies and diseases characterized by proliferation of activated T cells, such as graft-versus-host disease. DAB389IL-2 (ONTAK) is a ligand fusion toxin consisting of the full-length sequence of the IL-2 gene genetically fused to the enzymatically active and translocating domains of diphtheria toxin. DAB389IL-2 and its predecessor, DAB486IL-2, have demonstrated activity in a variety of diseases, including cutaneous T cell lymphoma (CTCL), psoriasis, rheumatoid arthritis, and HIV infection. Further clinical development of IL-2 fusion toxins in CTCL and other hematopoietic malignancies is predicated on identification of the high-affinity IL-2 receptor complex on the malignant cells and on a better understanding of the biological determinants of cytotoxicity of these molecules in vivo.