Mutations of ion channel genes have a major role in the pathogenesis of several epilepsies, confirming that some epilepsies are disorders due to the impairment of ion channel function (channelopathies). Voltage-gated Na(+) channels (VGSCs) play an essential role in neuronal excitability; it is, therefore, not surprising that most mutations associated with epilepsy have been identified in genes coding for VGSCs subunits. Epilepsies linked to VGSCs mutations range in severity from mild disorders, such as benign neonatal-infantile familial seizures and febrile seizures, to severe and drug-resistant epileptic encephalopathies. SCN1A is the most clinically relevant of all of the known epilepsy genes, several hundred mutations have been identified in this gene. This review will summarize recent advances and new perspectives on Na(+) channels and epilepsy. A better understanding of the genetic basis and of how gene defects cause seizures is mandatory to direct future research for newer selective and more efficacious treatments.