Our understanding of the potential role of sodium channels in multiple sclerosis (MS) has grown substantially in recent years. The channels have long had a recognized role in the symptomatology of the disease, but now also have suspected roles in causing permanent axonal destruction, and a potential role in modulating the intensity of immune activity. Sodium channels might also provide an avenue to achieve axonal and neuronal protection in MS, thereby impeding the otherwise relentless advance of permanent neurological deficit. The symptoms of MS are largely determined by the conduction properties of axons and these, in turn, are largely determined by sodium channels. The number, subtype and distribution of the sodium channels are all important, together with the way that channel function is modified by local factors, such as those resulting from inflammation (eg, nitric oxide). Suspicion is growing that sodium channels may also contribute to the axonal degeneration primarily responsible for permanent neurological deficits. The proposed mechanism involves intra-axonal sodium accumulation which promotes reverse action of the sodium/calcium exchanger and thereby a lethal rise in intra-axonal calcium. Partial blockade of sodium channels protects axons from degeneration in experimental models of MS, and therapy based on this approach is currently under investigation in clinical trials. Some recent findings suggest that such systemic inhibition of sodium channels may also promote axonal protection by suppressing inflammation within the brain.