Electrical activity in the heart depends critically on the interactions of multiple ion channels to coordinate the timing of excitation and contraction of the ventricles. Voltage-gated sodium channels underlie the rapid spread of impulses through the atria and ventricles, but the importance of sodium (Na+) channels to the control of the ventricular action potential has only most recently become apparent through the investigation of the relationship between mutation-induced clinical phenotypes and the altered function of mutant Na+ channels linked to inherited arrhythmias. Investigation into the structural basis of disease-associated mutations of the cardiac Na+ channel has led to the discovery of novel role of the Na+ channel carboxy-terminal (CT) domain in controlling channel inactivation. Intramolecular interactions between the carboxy-terminal domain and an intracellular peptide loop that forms the inactivation gate are required to minimize channel reopening during prolonged depolarization. Disruption of this interaction leads to persistent sodium channel current, action potential prolongation, and elevated risk of cardiac arrhythmia.