Drugs that block voltage-dependent Na+ channels are well known as local anaesthetics, antiarrhythmics and anticonvulsants. Recent studies show that these compounds also provide a powerful mechanism of cytoprotection in animal models of cerebral ischaemia, hypoxia or head trauma. In this article Charles Taylor and Brian Meldrum review evidence indicating that Na+ channel modulators are neuroprotective and describe recent ideas for the molecular sites of action of voltage-dependent Na+ channel blockers. Clinical trials with several compounds are now in progress for stroke and traumatic head injury, and the therapeutic potential for this group of compounds is discussed.