Rapid inactivation of sodium channels is crucial for the normal electrical activity of excitable cells. There are many different types of inactivation, including fast, slow and ultra-slow, and each of these can be modulated by cellular factors or accessory subunits. Fast inactivation occurs by a 'hinged lid' mechanism in which an inactivating particle occludes the pore, whereas slow inactivation is most likely to involve a rearrangement of the channel pore. Subtle defects in either inactivation process can lead to debilitating human diseases, including periodic paralyses in muscle, ventricular fibrillation and long QT syndrome (delayed cardiac repolarization) in the heart, and epilepsy in the CNS.