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Malaria is a devastating infectious disease and approximately half the world's population is at risk. Since vaccination is not yet available, small-molecule-based medicines are currently the best option for the treatment of patients suffering from malaria and combating the spread of infection. Development of resistance against existing drugs has created a need for new types of small molecules to be screened against Plasmodium falciparum, the etiological agent of malaria. The advent of diversity-oriented synthesis has enabled access to novel chemical structures. Evaluation of diversity-oriented synthesis compounds in phenotypic assays for growth inhibition of P. falciparum has resulted in novel hits, leads and even investigational drugs against malaria.