To date, there are no vaccines against any of the major parasitic diseases including leishmaniasis, and chemotherapy is the main weapon in our arsenal. Current drugs are toxic and expensive, and are losing their effectiveness due to parasite resistance. The availability of the genome sequence of two species of Leishmania, Leishmania major and Leishmania infantum, as well as that of Trypanosoma brucei and Trypanosoma cruzi should provide a cornucopia of potential new drug targets. Their exploitation will require a multi-disciplinary approach that includes protein structure and function and high throughput screening of random and directed chemical libraries, followed by in vivo testing in animals and humans. We outline the opportunities that are made possible by recent technologies, and potential problems that need to be overcome.