Nature Medicine, Published online: 19 August 2026; doi:10.1038/s41591-026-04624-y The emergence and spread of drug resistance threatens progress toward malaria control and elimination. We identified a rapidly spreading haplotype on chromosome 7 of Plasmodium falciparum that contains mutations and deletions in the px1 gene. This genomic locus is strongly associated with reduced susceptibility of P. falciparum to the primary first-line antimalarial drugs lumefantrine and dihydroartemisinin.