Although epilepsy is one of the most common neurological disorders and genetic factors are well known to play a role in response to antiepileptic drug (AED) treatment, the study of the pharmacogenetics of epilepsy has received relatively little attention and has not resulted in clinical applications to date. Our improved understanding of the pathogenesis of epilepsy and the mechanism of action of AEDs, together with recent advances in genetics and decreasing genotyping costs, have now paved the way for a more systematic application of pharmacogenetics in the field of epilepsy. It is hoped that the resulting knowledge will lead to a more rational treatment of epilepsy, development of more efficacious AEDs, and facilitation of clinical trials of new AEDs. However, there are formidable practical, methodological and theoretical hurdles to overcome before pharmacogenomic information will have any major utility in the clinical setting. Here, we discuss the evidence for a genetic contribution to AED response, review current knowledge in epilepsy pharmacogenetics and discuss potential future avenues with their implications, both for the clinical treatment of epilepsy and new AED development.