Ion channel dysfunction is an important mechanism that contributes to functional disability and axonal degeneration in multiple sclerosis (MS). Recent studies have revealed that there are complex rearrangements of voltage-gated Na(+) channels that occur with acute brain inflammation in MS, with up-regulation of primitive Na(+) channel isoforms such as Nav 1.2 during acute inflammation. While these changes may help support neural conduction, increased expression of 'persistent' Na(+) conductances and altered function of the Na(+)/K(+) pump may contribute to axonal degeneration in MS. Increased expression of K(+) channels due to demyelination has also been considered as a contributing factor to conduction failure in MS. Recent phase II and phase III clinical trials have demonstrated improvements in walking speed in patients receiving fampridine SR, a K(+) channel blocker. This medication appears to be well-tolerated with a low risk of serious adverse events and provides benefits in both relapsing and progressive forms of MS.