Sodium channels play an important role in the neuronal network by transmitting electrical impulses rapidly throughout cells and cell networks, thereby coordinating higher processes ranging from locomotion to cognition. These channels are large transmembrane proteins, which are able to switch between different states to enable selective permeability for sodium ions. For this process an action potential is needed to depolarize the membrane, and hence these channels are voltage-gated. It was not until the landmark studies of Hodgkin and Huxley1 in the early 1950s that the mechanism and function of sodium channels were revealed. Since then the development of the patch-clamp technique, which enables single-channel recordings, and the first cloning of a voltage-gated ion channel by Noda2 have enhanced our knowledge of sodium channel function and structure. In a similar manner, the antiepileptic drug phenytoin (1) and the neurotoxin tetrodotoxin (TTX) (2) were milestones in the recognition of the potential of neuronal sodium channel blockers in CNS-related disorders. It became apparent that voltage-gated sodium channels could be targeted, either selectively or in combination with other cellular processes, for the treatment of stroke, epilepsy, and several types of neuropathic pain. This review focuses on the latest developments in these areas, but we also refer the reader to several excellent reviews which cover the older literature more comprehensively.3-5