The identification of new antimalarial compounds is critical, as the Plasmodium parasite has developed resistance to all currently used drugs. One possibility to address this problem is to repurpose compounds with activity against other pathogens. We have characterized two exported epoxide hydrolases (EH) of Plasmodium falciparum, capable of hydrolysing bioactive epoxy-fatty acids into less active diols. To identify inhibitors of the parasite EHs we screened a library of adamantyl urea (AU)-based inhibitors, originally designed to target Mycobacterium tuberculosis (Mtb) EHs. Although some AU compounds inhibited the growth of malaria parasites, in vitro killing did not correlate with in vitro EH enzyme inhibition. However, killing of Plasmodium parasites correlated with Mtb killing. In Mtb the AU EH inhibitors have additional targets, with AU-resistant Mtb harboring mutations in the lipid transporter, MmpL3 (an antiporter). However, Plasmodium has no MmpL3 orthologue. Therefore, to investigate the target in the malaria parasite, we raised parasites that were resistant to the most potent AU inhibitor. Whole genome sequencing of two-independent selections revealed non-synonymous mutations in a different lipid transporter- a class 4, P-type lipid-transporting ATPase. Creation of a transgenic line overexpressing the ATPase confirmed that this protein confers parasite resistance to the AU inhibitor. The antimalarial action of another MmpL3 inhibitor (SQ109) was also investigated in Plasmodium parasites, with another parasite membrane transporter implicated in the mechanism of action/resistance. The hydrophobic nature of the antitubercular compounds may result in membrane accumulation and could explain why transporters were identified in resistance studies in both Mtb and Plasmodium.