In neurones and other electrically excitable tissues, voltage-dependent sodium (Nav) channels play an essential role in initiating and propagating the action potential. High-resolution structures of sodium channels have revealed new details concerning these macromolecules that provide insights into their ion-specificity and the conformational changes they undergo during the action potential. Nav channels typically exist in vivo as multicomponent macromolecular assemblies, containing auxiliary proteins that modulate channel gating and trafficking. The properties of some of these auxiliary proteins raise the possibility that Nav channels may exist as functionally coupled complexes. The close similarity between different Nav channel subtypes has frustrated attempts to develop isoform-specific inhibitors. However, the combination of new structural insights, together with antibody-based reagents and site-directed mutagenesis of protein-based toxin inhibitors, raises the possibility of higher target specificities than previously possible. Such reagents may form the basis for a new generation of Nav channel drugs.