Nav1.2 and Nav1.6 are two voltage-gated sodium channel isoforms found in adult CNS neurons. These isoforms differ in their electrophysiological properties, even though the major regions that are known to be involved in channel activation and inactivation are conserved between them. To determine if the terminal domains of these channels contributed to their activation and fast inactivation differences, we constructed chimeras between the two isoforms and characterized their electrophysiological properties. Exchanging the N-terminal 205 amino acids of Nav1.6 and the corresponding 202 amino acids of Nav1.2 completely swapped the V_1/2 of steady-state activation between the Nav1.2 and Nav1.6 channels in an isoform-specific manner. Exchanging the C-terminal 436 amino acids of Nav1.6 and the corresponding region of Nav1.2 altered the voltage dependence and kinetics of steady-state inactivation, but the changes did not reflect a direct transfer of inactivation properties between the two isoforms. Finally, the N- and C-terminal domains from Nav1.6 demonstrated functional cooperation. These results suggest that the terminal sequences of the sodium channel are important for isoform-specific differences between the channels.