Denileukin diftitox (ONTAK; Seragen Inc, San Diego, CA) is a fusion protein designed to direct the cytocidal action of diphtheria toxin to cells that overexpress the IL-2 receptor. The human IL-2 receptor exists in three isoforms: low (CD25), intermediate (CD122/CD132), and high (CD25/CD122/CD132) affinity. The high-affinity form of this receptor is expressed on activated T lymphocytes, activated B lymphocytes, and activated macrophages. A number of leukemias and lymphomas, including cutaneous T-cell lymphoma, chronic lymphocytic leukemia, and B-cell non-Hodgkin's lymphoma, express a component of the receptor. Ex vivo studies have shown that denileukin diftitox interacts with the high- and intermediate-affinity IL-2 receptor on the cell surface and undergoes internalization. Subsequent cleavage in the endosome releases the diphtheria toxin into the cytosol, which then inhibits cellular protein synthesis, resulting in rapid cell death. This article examines the clinical profile and potential benefits of denileukin diftitox in the treatment of cutaneous T-cell lymphoma and other hematologic disorders.