Na+ influx through voltage-gated Na+(NaV) channels drives the rapid rising phase of action potentials in neurons, cardiac myocytes, and skeletal muscle. There are nine NaV channel family members that share a common structure composed of four homologous transmembrane repeats, each containing six transmembrane segments, arranged around a central ion-permeating pore. The four transmembrane repeats are joined by intracellular loops, and the protein is capped on either end by intracellular N and C termini. These pore-forming subunits serve as the core of NaV channel macromolecular complexes containing components that allow targeting of NaV channels to specific subcellular domains such as the intercalated disks in cardiomyocytes or the axon initial segment in neurons and various regulatory proteins that fine-tune channel function. Among these critical regulatory proteins is calmodulin (CaM), which binds directly to the channel’s intracellular C-terminal domain (CTD). Although CaM is best appreciated for its ability to act as an intracellular Ca2+ transducer, for NaV channels growing evidence shows that Ca2+-free CaM also functions as both a structural component as well as a Ca2+ sensor, but the specific roles for CaM in NaV channel function are still not clearly understood (Pit t and Lee, 2016).