Malaria is a persistent and successful global disease that threatens half of the world s population and kills up to a million people each year. The developing world has urgently needed new, safe, effective, and affordable antimalarial drugs since the demise of chloroquine due to the emergence of resistant P. falciparum strains. Strides have been made to develop an array of antimalarial agents with artemisinin-based combination therapies (ACTs) providing a major breakthrough, succeeding in more than 90 of the malaria cases. However, artemisinin effectiveness appears to be decreasing along the Thai- Combodia border, threatening these recent gains. The limitations of current antimalarial chemotherapy underscore the need for novel drugs, ideally directed against innovative therapeutic targets. The completion of the malaria genome project has opened up channels to search for new targets in the parasite. Despite the identification of many essential genes and extensive efforts to understand the biology of the parasite, very few unique validated targets have been identified. Hence, the contemporary challenge is to blend our knowledge of malaria genomics and drug discovery.