Voltage-gated sodium (Na v ) channels in cardiomyocytes are localized in specialized membrane domains that optimize their functions in propagating action potentials across cell junctions and in stimulating voltage-gated calcium channels located in T tubules. Mutation of the ankyrin-binding site of Na v 1.5, the principal Na v channel in the heart, was previously known to cause cardiac arrhythmia and the retention of Na v 1.5 in an intracellular compartment in cardiomyocytes. Conclusive evidence is now provided that direct interaction between Na v 1.5 and ankyrin-G is necessary for the expression of Na v 1.5 at the cardiomyocyte cell surface.