Kaposi's sarcoma (KS) is an angioproliferative disease of multifactorial origin arising in different clinic-epidemiologic forms, which show the same histopathological features. It generally starts as a hyperplastic reactive-inflammatory and angiogenic process, which may evolve into monomorphic nodules of KS cells that can be clonal (late-stage lesions) and resemble a true sarcoma. Infection with the human herpesvirus 8, cytokine- and angiogenic factor-induced growth together with an immuno-dysregulated state represent fundamental conditions for the development of this tumor. Several local therapies are used to eradicate early and confined skin lesions, whereas widely disseminated, progressive or symptomatic disease requires a more aggressive treatment. Although different chemotherapeutic agents have been used to treat aggressive KS, the growing understanding of the pathogenetic factors participating in KS development has provided a strong rationale for using less- or non-cytotoxic agents that block the mechanisms involved in KS pathogenesis. The angiogenic nature of KS makes it particularly suitable for using therapies based on anti-angiogenic agents. Of note on this goal, recent studies indicate that the highly active anti-retroviral therapy, including at least one human immunodeficiency virus (HIV) protease inhibitor (PI), is associated with a dramatic decrease in the incidence of AIDS-KS and with a regression of KS in treated individuals. Consistent with this, results from preclinical studies indicate that PIs have potent and direct anti-angiogenic and anti-KS activities, suggesting that they should be further investigated, alone or combined with other therapies, as a novel treatment for KS in both HIV seropositive or seronegative individuals.