Despite a large number of new drugs, ~30% of patients remain refractory to anti-epileptic drugs (AEDs). Overcoming the mechanisms of pharmacoresistance requires a precise understanding of how AEDs interact with their targets in control and epileptic tissue. We have discovered in the past shown that transient Na+ channels in human and experimental epilepsy exhibit a key change that renders them less susceptible to use-dependent block by conventional Na+ channel blocking AEDs such as carbamazepine (CBZ). We are currently addressing the molecular-level changes that underlie the emergence of ‚AED-resistant‘ Na+ channels. We will explore the relevance of defined molecular changes using gene therapy approaches in animal models of epilepsy.