ABSTRACT.    In the battle against malaria, an innovative new therapy has emerged from a french collaborative discovery project. A series of ferrocenic analogue-based drugs (including quinine, mefloquine, artemisinine, mepacrine and chloroquine) was designed, synthesized, and screened for antimalarial activity. The best candidate among the whole series was Ferroquine, a chloroquine-like drug where the ferrocene is covalently flanked by the 4-aminoquinoline and the alkylamine. Ferroquine is extremely active against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum laboratory strains and field isolates. Based on experiments using animal and human hepatic models, the metabolic pathway of ferroquine, was dissected. The mechanism of action of ferroquine should be in part similar to that of chloroquine, namely involving hematin as the drug target and inhibition of hemozoin formation. Previous investigations showed that the metallocene altered the shape, volume, lipophilicity, basicity and electronic profile of the parent molecule and consequently, its pharmacodynamic behavior. Until today, attempts at trying to induce in vitro or in vivo Ferroquine resistance failed. The next step will be a phase II trial to compare results with those of standard treatment. The present study illustrates the growing importance of bioorganometallics in drug discovery.