Modulation of voltage-gated sodium channels (VGSC) can have a major impact on cell excitability. Analysis of calmodulin (CaM) binding to GST-fusion proteins containing the C-terminal domains of Nav1.1-Nav1.9 indicates that some of the tetrodotoxin-sensitive VGSC isoforms, including NaV1.4 and NaV1.6, are able to bind CaM in a calcium-independent manner. Here we demonstrate that association with CaM is important for functional expression of NaV1.4 and NaV1.6 VGSCs. Disrupting the interaction between CaM and the C terminus of NaV1.4 and NaV1.6 channels reduced current amplitude by 99 and 62%, respectively. Overexpression of CaM increased the current generated by Nav1.4 and Nav1.6 C-terminal mutant constructs that exhibited intermediate current densities and intermediate binding affinities for CaM, demonstrating that this effect on current density was directly dependent on the ability of the C terminus to bind CaM. In addition to the effects on current density, calmodulin also was able to modulate the inactivation kinetics of Nav1.6, but not Nav1.4, currents in a calcium-dependent manner. Our data demonstrate that CaM can regulate the properties of VGSCs via calcium-dependent and calcium-independent mechanisms and suggest that modulation of neuronal sodium channels may play a role in calcium-dependent neuronal plasticity.