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Malaria remains a global health burden partly due to parasite resistance to first-line therapeutics. The molecular chaperone heat shock protein 90 (Hsp90) has emerged as an essential protein for blood-stage parasites, but details about its function during malaria's elusive liver stage are unclear. We used target-based screens to identify compounds that bind to and human Hsp90, which revealed insights into chemotypes with species-selective binding. Using cell-based malaria assays, we demonstrate that all identified Hsp90-binding compounds are liver- and blood-stage inhibitors. Additionally, the Hsp90 inhibitor SNX-0723 in combination with the phosphatidylinositol 3-kinase inhibitor PIK-75 synergistically reduces the liver-stage parasite load. Time course inhibition studies with the Hsp90 inhibitors and expression analysis support a role for Hsp90 in late-liver-stage parasite development. Our results suggest that Hsp90 is essential to liver- and blood-stage parasite infections and highlight an attractive route for development of species-selective Hsp90 inhibitors that may act synergistically in combination therapies to prevent and treat malaria.