HIV protease inhibitors are antiretroviral drugs that block the enzyme required for production of infectious viral particles. Although these agents have been designed to selectively bind to the catalytic site of HIV protease, evidence indicates that other cellular and microbial enzymes and pathways are also affected. It has been reported that patients treated with highly active anti-retroviral therapy (HAART) containing a protease inhibitor may be at reduced risk of Kaposi's sarcoma (KS) and some types of non-Hodgkin lymphomas; some disease regressions have also been described. Here we review recent data showing that several widely used protease inhibitors, including indinavir, saquinavir, ritonavir, and nelfinavir, can affect important cellular and tissue processes such as angiogenesis, tumour growth and invasion, inflammation, antigen processing and presentation, cell survival, and tissue remodelling. Most of these non-HIV-related effects of protease inhibitors are due to inhibition of cell invasion and matrix metalloprotease activity, or modulation of the cell proteasome and NFkappaB. These elements are required for development of most tumours. Thus, by direct and indirect activities, protease inhibitors can simultaneously block several pathways involved in tumour growth, invasion, and metastasis. These findings indicate that protease inhibitors can be exploited for the therapy of KS and other tumours that occur in both HIV-infected and non-infected individuals. A multicentre phase II clinical trial with indinavir in non-HIV-associated KS is about to start in Italy.