The high concentration of the tyrosine-rich polypeptide, neuropeptide Y (NPY), and the increase in the number of its receptor subtypes that have been characterized in the brain, raise the question of a functional role for NPY in the CNS. In addition to its peripheral actions on cardiovascular regulation, much attention has, therefore, been devoted to the CNS effects of NPY because of its stimulatory properties on food intake, its role in anxiolysis and its putative involvement in memory retention. Emerging evidence points to an important role for NPY in the regulation of neuronal activity both under physiological conditions and during pathological hyperactivity such as that which occurs during seizures. This article reviews recent studies that have shown the changes induced by seizures in the level and distribution of NPY, its receptor subtypes and their respective mRNAs in rat forebrain. Biochemical and electrophysiological findings in experimental models and tissue from human epilepsy sufferers suggest that NPY-mediated neurotransmission is altered by seizures. The pharmacological evidence and functional studies in NPY knockout mice highlight a crucial role for endogenous NPY, acting on different NPY receptors, in the control of seizures.