The main cardiac voltage-gated Na+ channel, Nav1.5, plays a key role in generation of the cardiac action potential (cardiac excitability) and propagation of the electrical impulse in the heart (cardiac conduction). During the past decade, numerous mutations in SCN5A, the gene, encoding Nav1.5, were found in patients with different pathologic cardiac phenotypes such as the congenital long QT syndrome type 3, Brugada syndrome, and progressive cardiac conduction defect (or Lenègre-Lev disease). These mutations define a sub-group of Nav1.5 / SCN5A-related cardiac channelopathies. Recent works have suggested that Nav1.5 is part of several multi-protein complexes located in different membrane compartments of the cardiac cells. In some instances, the genes of these regulatory proteins were also found to be mutated in patients with inherited forms of cardiac arrhythmias. The proteins that associate with Nav1.5, and form these complexes, can be classified as 1) anchoring/adaptor proteins, 2) enzymes interacting with and modifying the channel, and 3) proteins modulating the biophysical properties of Nav1.5 upon binding. The purpose of this short article is to review the proposed roles of these interactions. These recent observations indicate that the expression level, cellular localization, and activity of Nav1.5 are finely regulated by complex molecular mechanisms that we are only starting to elucidate.