The endogenous NPY system in the brain is centrally involved in seizure regulation. The present paper reviews the evidence that exogenously applied NPY receptor ligands can inhibit epileptic seizures in various rodent in vitro and in vivo models. Agonists at Y2 and/or Y5 receptors and antagonists at Y1 receptors appear to inhibit seizures, depending on the seizure model studied. Although progress has been made, further studies are needed using transgenic animals as well as novel selective agonists and antagonists to firmly identify the NPY receptors mediating antiepileptic effects. This may lead to the development of future antiepileptic drug treatments targeting the NPY system.