Voltage-gated sodium channels are membrane proteins that initiate action potentials in neurons following membrane depolarization. Members of this family show differential distribution at the subcellular level. The mechanisms underlying the targeting of these isoforms are not understood. However, their specificity is important because the isoforms can change the excitability of the membrane due to differences in their electrophysiological properties. In this study, chimeras generated between Na_V1.2 and Na_V1.6 were used to test channel domains for sequence that would allow Na_V1.2 to localize to unmyelinated axons when Nav1.6 could not. We show that the N-terminal 202 amino acids of the Na_V1.2 channel can mediate membrane domain-specific sorting in polarized epithelial cells and are necessary but not sufficient for localizing the isoform to the axons of cultured neurons. The domain-sorting signal is in the region between amino acids 110–202 of the Na_V1.2 channel. The C-terminal 451 amino acids of Na_V1.2 likely contain determinants that interact with neuron-specific factors to direct Na_V1.2 to the axon.