Malaria remains a significant cause of morbidity and mortality worldwide with an estimated 1 million people dying from this disease every year. Drug resistance is widespread, and with a safe and effective vaccine still many years away, new chemotherapeutic agents are required to ensure that cheap and effective treatment is widely available. We have demonstrated that some antiretroviral protease inhibitors (APIs) kill malaria parasites in vitro and in vivo at clinically relevant concentrations, a finding whose clinical significance we are now determining in multi-centre clinical trial in malaria endemic regions of Africa. While our in vitro isobologram data demonstrate that the antimalarial activity of the API's is likely to benefit those people who are co-infected with HIV and malaria, they are not appropriate for first-line antimalarial agents in their own right. Nevertheless, the antimalarial target of these anti-HIV drugs represents a completely new approach to the development of malaria parasite-specific therapies. More recent data now demonstrate that APIs have an activity against a broad range of parasite developmental stages, and that these drugs kill malaria parasites by acting on an uncharacterized non-digestive vacuole plasmepsin that is yet to be exploited as a potential target for antimalarial drug development.