The coincident cloning of the voltage-gated Na channel from the electric eel electroplax and development of patch–clamp methodology has allowed an explosive phase of investigation into the structural basis of cardiac Na channel function. Recognizing the importance of structural motifs that underlie gating (charged S4 segments, III–IV linker) and permeation (P-loops) have complemented new molecular information surrounding inherited cardiac arrhythmias, such as the chromosome 3-linked form of the long QT syndrome. Although the proarrhythmic potential recognized in the CAST trial slowed the development of class I antiarrhythmic agents, our emerging understanding of the molecular pharmacology of Na channels may motivate strategies for Na-channel drug discovery that involve targeting particular structural domains.