Na(v)1.5, the major cardiac voltage-gated Na(+) channel, plays a central role in the generation of the cardiac action potential and in the propagation of electrical impulses in the heart. Its importance for normal heart function has been recently exemplified by reports of numerous mutations found in the gene SCN5A--which encodes Na(v)1.5--in patients with various pathologic cardiac phenotypes, indicating that even subtle alterations of Na(v)1.5 cell biology and function may underlie human diseases. Similar to other ion channels, Na(v)1.5 is most likely part of dynamic multiprotein complexes located in the different cellular compartments. This review focuses on five intracellular proteins that have been recently reported to directly bind to and contribute to the regulation of Na(v)1.5: ankyrin proteins, fibroblast growth factor homologous factor 1B, calmodulin, Nedd4-like ubiquitin-protein ligases, and syntrophin proteins.