Every cell within living organisms actively maintains an intracellular Na+ concentration that is 10–12 times lower than the extracellular concentration. The cells then utilize this transmembrane Na+ concentration gradient as a driving force to produce electrical signals, sometimes in the form of action potentials. The protein family comprising voltage-gated sodium channels (NaVs) is essential for such signaling and enables cells to change their status in a regenerative manner and to rapidly communicate with one another. NaVs were first predicted in squid and were later identified through molecular biology in the electric eel. Since then, these proteins have been discovered in organisms ranging from bacteria to humans. Recent research has succeeded in decoding the amino acid sequences of a wide variety of NaV family members, as well as the three-dimensional structures of some. These studies and others have uncovered several of the major steps in the functional and structural transition of NaV proteins that has occurred along the course of the evolutionary history of organisms. Here we present an overview of the molecular evolutionary innovations that established present-day NaV α subunits and discuss their contribution to the evolutionary changes in animal bodies.