Kaposi's sarcoma is a highly lethal tumor in patients with sexually acquired AIDS. A number of etiologic agents have been implicated in the development of this disease in this patient population and there is ample evidence that aberrant production of and responsiveness to KS tumor and host cell-derived cytokines plays a central role in the pathogenesis of AIDS-KS. In this review we propose that aberrant expression SF and c-met is central to the pathogenesis of KS. KS is a serious and life-threatening consequence for many patients with AIDS. Unfortunately, current therapeutic strategies for the treatment of this complex neoplasm have met with only limited success. In view of the poor survival rates for AIDS-KS patients which continue to decline at an alarming rate, it is eminently clear that a better understanding of the etiology and pathogenesis of this form of KS is needed if novel therapeutic strategies designed to successfully combat this disease are to be developed. If our hypothesis is validated, one could envision several approaches whereby the modulation of SF/c-met function or production might lead to a reduction in the incidence and severity of KS lesions. Antibody therapy directed against either SF-producing tumor cells or against the c-met receptor might decrease the incidence of new tumors by limiting their clonal expansion and lead to regression of established tumors by blocking SF-mediated tumor cell proliferation and neovascularization. It might also be possible to suppress production of SF or accessory cytokines involved in the induction SF production and thus short circuit SF/c-met growth-promoting effects. We have outlined a novel hypothesis for understanding the mechanism underlying the development of AIDS-associated KS. This is most certainly not the whole story, however. Clearly, other cytokines and alterations in natural host defenses and the immune system contribute significantly to the development of AIDS-associated KS. We believe, however, that recognition of SF/c-met as a participant in this disease is necessary if we are to more fully understand the pathogenesis of AIDS-associated KS.