The cardiac voltage-gated Na⁺ channel Na_v1.5 generates the cardiac Na⁺ current (INa). Mutations in SCN5A, the gene encoding Na_v1.5, have been linked to many cardiac phenotypes, including the congenital and acquired long QT syndrome, Brugada syndrome, conduction slowing, sick sinus syndrome, atrial fibrillation, and dilated cardiomyopathy. The mutations in SCN5A define a sub-group of Na_v1.5/SCN5A-related phenotypes among cardiac genetic channelopathies. Several research groups have proposed that Na_v1.5 may be part of multi-protein complexes composed of Na_v1.5-interacting proteins which regulate channel expression and function. The genes encoding these regulatory proteins have also been found to be mutated in patients with inherited forms of cardiac arrhythmias. The proteins that associate with Na_v1.5 may be classified as (1) anchoring/adaptor proteins, (2) enzymes interacting with and modifying the channel, and (3) proteins modulating the biophysical properties of Na_v1.5 upon binding. The aim of this article is to review these Na_v1.5 partner proteins and to discuss how they may regulate the channel's biology and function. These recent investigations have revealed that the expression level, cellular localization, and activity of Na_v1.5 are finely regulated by complex molecular and cellular mechanisms that we are only beginning to understand.