A substantial amount of experimental evidence implicates neuropeptide Y (NPY) in the pathophysiology of epilepsy. Over the past 20 years, remarkable progress has been made in unraveling the mechanisms and receptors involved in the anticonvulsant effect of this abundantly expressed neuropeptide. Activation of Y2 and/or Y5 receptors and blockade of Y1 receptors in the central nervous system suppresses seizures in a variety of animal seizure models. Orally available, brain penetrating Y2 and/or Y5 agonists, and possibly Y1 antagonists, may therefore constitute a novel class of antiepileptic drugs, which could greatly benefit patients with medically refractory epilepsy. Significant progress has been made in identifying non-peptidergic Y1 antagonists that fulfill these criteria, but suitable Y2 and/or Y5 agonists have proven to be more elusive. Innovative oral and parental drug delivery strategies which are currently under development may offer a means of using the more readily available peptidergic NPY receptor ligands in a clinical setting. Finally, gene therapy, antisense probes or RNA interference strategies which alter the expression of NPY or its receptors in specific brain regions may also be of use in the treatment of epilepsy, but will probably benefit a smaller subgroup of epilepsy patients, since they typically require an invasive procedure.