Tim Anderson and colleagues characterize the genetic and molecular basis of oxamniquine (OXA) resistance in Schistosoma mansoni, a trematode parasite (Science doi:10.1126/science.1243106, 21 November 2013). They performed linkage mapping in the second-generation progeny of a cross between a sensitive and a resistant parasite, identifying a single quantitative trait locus (QTL) that included 16 candidate genes. They used a biochemical complementation assay to test which of the candidate genes produced a protein that is able to convert OXA, a pro-drug, to an active form of the drug as present in sensitive but not resistant parasites. They found that Smp_089320 activated OXA in extracts from resistant parasites and confirmed its role in OXA resistance by showing that RNA interference knockdown of Smp_089320 in drug-sensitive parasites resulted in an increase in resistance. They found that the Smp_089320 protein in sensitive but not resistant strains showed sulfonation activity, identifying a mechanism for the drug in which it acts as a sulfotransferase that activates OXA. Finally, the authors determined the crystal structure of Smp_089320 protein from sensitive parasites with OXA bound and suggest that the mechanism of resistance involves disruption of the drug-protein interaction in resistant strains. Comparative and phylogenetic analysis with other schistosomes also suggests the basis for the species specificity in OXA drug action.