Malaria elimination has recently been reinstated as a global health priority but current therapies seem to be insufficient for the task. Elimination efforts require new drug classes that alleviate symptoms, prevent transmission and provide a radical cure. To develop these next-generation medicines, public–private partnerships are funding innovative approaches to identify compounds that target multiple parasite species at multiple stages of the parasite life cycle. In this Review, we discuss the cell-, chemistry-and target-based approaches used to discover new drug candidates that are currently in clinical trials or undergoing preclinical testing.