In the past, the study of KS pathogenesis has been hampered by the lack of in vitro and in vivo experimental systems. Recently, the establishment of long-term cultures of KS spindle cells and the development of animal models have allowed a variety of studies on the pathobiology of the disease. The results from these studies, reviewed herein, indicate that KS is a cytokine-mediated disease and that inflammatory and angiogenic cytokines and the HIV-1 Tat protein cooperate in its induction and progression in HIV-1-infected individuals.