The use of anti-HIV drugs as cancer treatments is not new. Azidothymidine was studied as an antineoplastic in the 1990s, but despite promising in vitro data, clinical trials showed little antitumour activity. HIV protease inhibitors were developed in the early 1990s, and their subsequent incorporation into highly active antiretroviral therapy (HAART) has profoundly changed the natural history of HIV infection. The potential antitumour properties of these drugs have been investigated because of their success in treating HIV-related Kaposi’s sarcoma. HAART’s effects on Kaposi’s sarcoma did not always correlate with immune reconstitution, and activity against other solid and haematological malignancies has been established. Inhibition of tumour-cell invasion and angiogenesis were properties first ascribed to inhibition of HIV protease; however, they have pleiotropic antitumour effects, including inhibition of inflammatory cytokine production, proteasome activity, cell proliferation and survival, and induction of apoptosis. HIV protease inhibitors are thus a new class of anticancer drugs with multiple effects, and other anti-HIV drugs might hold similar promise.