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Previously proposed as antichagasic agents, several lipophilic o-naphthoquinones (o-NQs) such as β-lapachone have proven potent inhibitors of human cancer cell growth, awakening renewed interest in those quinones. Accordingly, cytotoxicity mechanisms of o-NQs and similar molecules, including β-lapachone, its CG-analogues and mansonones, are now reviewed. Those quinones interact with enzymatic systems, such as rat liver and trypanosomatid NADPH-P450 reductases. Most of the assayed o-NQs are potent inhibitors of Trypanosoma cruzi, Crithidia fasciculata and Leptomonas Seymouri growth. Their action is in all probability dependent on the quinone redox-cycling that yields reactive oxygen species (ROS). The initial reduction of the quinone to quinol is followed by the quinol oxidation by molecular oxygen, that produces the corresponding semiquinone. The semiquinone further reacts with molecular oxygen thus producing superoxide anion, hydrogen peroxide and hydroxyl radicals, all remarkable for their cytotoxicity. As a result of those reactions, oxidative damage occurs involving cellular ATP depletion, thiol depletion, drop in DNA, RNA and cell protein synthesis and enhancement of the same macromolecules degradation. Similar effects are observed with isoxazolylnaphthoquinone-imines. Vicinal carbonyl groups and the pyrane ring are essential for o-NQs cytotoxic, as shown by the lesser activity or inactivity (according to the assay system) of the β-naphthoquinone α-lapachone and menadione. At variance with the above summarized effects, o-NQs prevent liver microsomal lipid and cytochrome P450 peroxidation. The action of o-NQs in programmed cell death (apoptosis) is discussed.