Interferon alfa (IFNalpha) was one of the first agents to be used therapeutically in AIDS-associated Kaposi's sarcoma (KS) more than 25 years ago, and induces tumor regression in a subset of patients. Although much has been learned about the clinical role of IFNalpha in KS treatment, little is currently known about the mechanism(s) by which IFNalpha causes KS regression. This is despite a growing understanding of both KS pathogenesis and relevant IFNalpha activities. To a large extent other agents have supplanted IFNalpha as treatments for KS, but there may still remain a therapeutic role for IFNalpha, possibly in combination with other agents targeting angiogenesis and/or HHV-8-encoded human gene homologs that encode proteins involved in cell cycle regulation and signaling.