Voltage-gated Na(+) channels are heteromeric membrane glycoproteins responsible for the generation of action potentials. A number of diverse lipid-soluble neurotoxins, such as batrachotoxin, veratridine, aconitine, grayanotoxins, pyrethroid insecticides, brevetoxins and ciguatoxin, target voltage-gated Na(+) channels for their primary actions. These toxins promote Na(+) channel opening, induce depolarization of the resting membrane potential, and thus drastically affect the excitability of nerve, muscle and cardiac tissues. Poisoning by these lipid-soluble neurotoxins causes hyperexcitability of excitable tissues, followed by convulsions, paralysis and death in animals. How these lipid-soluble neurotoxins alter Na(+) channel gating mechanistically remains unknown. Recent mapping of receptor sites within the Na(+) channel protein for these neurotoxins using site-directed mutagenesis has provided important clues on this subject. Paradoxically, the receptor site for batrachotoxin and veratridine on the voltage-gated Na(+) channel alpha-subunit appears to be adjacent to or overlap with that for therapeutic drugs such as local anaesthetics (LAs), antidepressants and anticonvulsants. This article reviews the physiological actions of lipid-soluble neurotoxins on voltage-gated Na(+) channels, their receptor sites on the S6 segments of the Na(+) channel alpha-subunit and a possible linkage between their receptors and the gating function of Na(+) channels.