This review compares the knowledge accumulated in different aspects of the expression and function of Nav1.4 and Nav1.5 α-subunits, and focuses on “homologous” mutations i.e., in the same (aligned) amino acids of the skeletal muscle Nav1.4 and of the cardiac Nav1.5 leading to a large range of muscular and cardiac disorders also called channelopathies. Here, SCN5A is linked to channelopathy.