New therapeutic agents for the treatment of malaria, the world's most deadly parasitic disease, are urgently needed. Malaria afflicts 300-500 million people and results in 1-2 million deaths annually and more than 85% of all malaria related mortality is to young children and pregnant women in Sub-Saharan Africa. The emergence of multi-drug resistant parasites, particularly in Plasmodium falciparum (especially to chloroquine) has led to the resurgence and spread of malaria in large parts of the developing world. An ideal new antimalarial agent should: be specific for the parasite, target a process that is essential for parasite growth, and be highly active against multi-drug resistant parasite strains. Historically, chloroquine was the most important and effective antimalarial drug due to its extremely low cost, high efficacy and is a process unique to the parasite. In light of these properties chloroquine is still the drug to emulate. There is now considerable evidence to suggest that chloroquine and related 4-aminoquinoline compounds act by interfering with hemozoin formation in the malaria parasite. Thus, what is currently needed is new chemotherapeutics that target hemozoin formation in the parasite. The most effective method to find such new chemotherapeutic agents is to develop new target-based assays that will be used to perform high-throughput screening of structurally diverse small molecule libraries. This proposal outlines the development of a heme crystallization assay that is technically simple, robust, and compatible with the automation necessary for HTS to identify inhibitory small molecules from structurally diverse small molecule libraries. New therapeutic agents for the treatment of malaria, the world's most deadly parasitic disease, are urgently needed. Here we will develop a new target-based assay to screen structurally diverse small molecule libraries to identify new antimalarial agents to kill the parasite.