PIP: Kaposi's sarcoma (KS) is a complex neoplasm of cells of endothelial and fibroblast origin, whose proliferation is maintained by the viral product Tat, cytokines, and maybe environmental factors. It was among the first noted clinical manifestations of AIDS and remains the most common malignancy observed in patients infected with HIV, yet an optimal treatment strategy remains to be identified. The authors discuss current options and future directions for the systemic treatment of KS. They do not, however, address local forms of treatment. It is concluded that angiogenesis inhibitors may provide a novel therapeutic approach in the near future, while single agent cytotoxic chemotherapy and combination chemotherapy may induce remissions in the majority of patients along with relief from the morbidity of edema, disfigurement, and pain. Interferon is effective mainly in patients who are not severely immunocompromised. Finally, systemic therapy for AIDS-associated KS must be integrated with antiretroviral therapy, prophylaxis for opportunistic infections, and appropriate hematological support. Sections explore the etiology and pathogenesis of KS, rationale for systemic treatment, single-agent chemotherapy, combination chemotherapy, chemotherapy and antiretroviral agents, interferon, interferon and antiretroviral therapy, interferon and chemotherapy, other biological agents, angiostatic compounds, and anti-Tat therapy. Innovative treatment approaches to KS may ultimately prove applicable to many other neoplastic disorders.