This article reviews developments over nearly 15 years in the application of interferon-alpha (IFN-alpha) to the treatment of Kaposi's sarcoma (KS) in patients with acquired immunodeficiency syndrome (AIDS). The initial success of IFN treatment for selected patients with AIDS-associated KS occurred before identification of the human immunodeficiency virus (HIV) and in the absence of any coherent view of KS pathogenesis. A more comprehensive understanding of the biology of both AIDS and KS, together with increased knowledge of the biologic effects of IFN and therapeutic advances in the treatment of HIV infection, have made IFN therapy for KS both more rational and more successful. There is every reason to believe that the current results with IFN for KS can be improved on by capitalizing on recent improvements in HIV therapy and the availability of specific inhibitors of angiogenic cytokines. I sincerely thank the Milstein family and my colleagues in the International Society for Interferon and Cytokine Research (ISICR) for recognizing this work, which is the product of many collaborations between clinical and basic scientists in my own institution and elsewhere.