Action potential is a form of electric signaling responsible for conducting neural firing in organisms. Voltagegated sodium channels (VGSCs) are key molecules contributing to the initiation of action potential, playing an indispensable role in electric excitation and firing neurons. Briefly, the overall excitory activities and signalling input/output process of synaptic transmission in neurons mostly depends on VGSCs. Meanwhile, VGSCs are targets of numerous natural neurotoxns or synthesize compounds. By blocking or modulating the ion permeable selectivity and shifting the structurefunction balance of channel gating, clinical pathology or relief from severe syndromes result. This article gives a general overview of endogenous regulation and exogenous modulation of VGSCs, which may highlight the physiological/pathological status and targetted phamacolgical/toxicological values of VGSCs.