Our group has pioneered the biological chemistry and the molecular understanding of 2methyl-1,4-naphthoquinone (menadione) derivatives. These are described as redox-active agents catalyzing various NADPH-consuming reactions, that are the basis of the antiparasitic activities of the series. Then, by introducing structural diversity on the menadione core, we selected a 3-benzylmenadione (benzylMD) scaffold as a chemotype with cross-pathogen activity. Previous studies on the mode of action of benzylMD revealed that this scaffold disturbs the redox balance of protozoan parasites by acting as a subversive substrate of NADPHdependent oxido-reductases. The first success has been obtained with the discovery of the potent antimalarial early lead benzylMD, named plasmodione, active against young asexual stages of P. falciparum in strains with varying degrees of drug resistance, and in sexual stages (early gametocytes). It has a safe toxicological profile for possible human use, including towards G6PD-deficient populations. We have shown that the antimalarial selectivity of benzylMD comes largely from its specific bioactivation within Plasmodium parasitized-red blood cells through a cascade of NADPH-dependent redox reactions generating a key 3benzoylmenadione metabolite (benzoylMD). Our approach to generate oxidative stress specifically in parasitized human erythrocytes has been validated as a novel and efficient strategy to combat malarial parasites, mimicking the conditions of a parasite developing in G6PD-deficient red blood cells of cerebral malaria-protected populations.