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Kaposi sarcoma (KS) remains the most commonly diagnosed cancer in HIV-infected patients. Although several chemotherapeutic agents have proven effective in controlling KS, the growing understanding of the factors contributing to the development of KS has provided a stronger rationale for using noncytotoxic agents that influence the mechanisms involved in KS pathogenesis. Two such agents, interferon and thalidomide, have shown activity against KS in clinical trials and have the potential to influence multiple steps believed to be important in KS development and progression. Studies are ongoing to explore the optimal way to use these agents and their mechanisms of action.