Neuropeptide Y (NPY) is contained in at least four types of GABAergic interneurons in the dentate gyrus, many of which also contain somatostatin and give rise to the dense NPY innervation of the dentate outer molecular layer. In humans but not rats, minute amounts of NPY are also normally expressed in dentate granule cells, while seizure activity in rats induces robust NPY expression in granule cells. Y1 and Y2 receptors are the most abundant NPY receptors expressed in the dentate gyrus. Y1 receptors are postsynaptic receptors, primarily located on granule cell dendrites in the molecular layer and some interneurons, while Y2 receptors are presynaptic receptors mediating inhibition of glutamate release, and potentially that of NPY and GABA depending on their presynaptic localization, and may also be expressed on some hilar interneurons. In humans, monkeys and mice, Y2 receptors are also present on mossy fibers, but not in most rat species, though functional evidence suggests their presence. Hilar interneurons containing NPY degenerate in temporal lobe epilepsy and in Alzheimer's disease and reduced levels of NPY in dentate hilus are associated with depression. By activating Y1 receptors, NPY also exerts powerful neuroproliferative effects on subgranular zone progenitor cells, increasing the number of newly born granule cells in the adult dentate gyrus. Functionally, NPY exerts anticonvulsive actions mediated by Y2 receptors at mossy fiber terminals, but there are no presynaptic responses to NPY at perforant path inputs to dentate granule cells in rats or mice. NPY also has potentially complicated actions on NPY-containing interneurons. Elevated expression of NPY in mossy fibers of the rat, sprouting of NPY interneurons in the human dentate, and over-expression of Y2 receptors in mossy fibers indicate an anticonvulsive role of endogenous NPY in epilepsy. However, the physiological role of NPY in the healthy dentate gyrus remains unclear.