A programme for developing new drugs for the treatment of Plasmodium falciparum malaria is targeted against the essential phospholipid metabolism of the intra-erythrocytic stages of the parasite. Blockage of the choline transporter that provides the intracellular parasite with choline, a precursor required for synthesis of phosphatidylcholine, the major phospholipid of the parasite, seems to hold the most promise. Molecules with the ability to interfere with this step, whose structures have been optimised using structure-activity criteria, have been synthesised. The antimalarial activity of the compounds produced so far, which have in-vitro activities in the ng/ml or nanomolar ranges, appears satisfactory. The present compounds are also active, in vitro, against parasites resistant to the antimalarial drugs already in clinical use. In vivo, one of the compounds, G2S, successfully cleared high parasitaemias of murine parasites in mice and of P. falciparum in Aotus monkeys. There were no recrudescences in the treated monkeys and the therapeutic index of the drug in monkeys is probably > 50. Targeting of phospholipid metabolism therefore appears to be a rational and promising approach to the development of new antimalarial drugs.