Malaria is one of the most devastating diseases in the world, affecting almost 225 million people a year, and causing over 780,000 deaths, most of which are children under the age of 5 years. Following the recent call for the eradication of the disease, supported by the WHO, there has been increasing investment into antimalarial drug-discovery projects. These activities are aimed at generating the next generation of molecules focused on the treatment and transmission-blocking of Plasmodium falciparum and Plasmodium vivax endo- and exo-erythrocytic stages of the parasite. This article summarizes the current top-level thinking regarding the prosecution of such endeavors and the disease-specific considerations in project planning.