Neuropeptide Y (NPY) is present in the hypothalamus, where it is believed to play a key role in the control of food intake. Evidence for this assertion has come from studies demonstrating that acute administration of NPY into the hypothalamus or into the brain ventricles leads to increased food intake. In the case of chronic administration, the hyperphagic effects of NPY are prolonged leading to the development of an obese state. NPY levels in the hypothalamus are temporally correlated with food intake and are markedly elevated in response to energy depletion. However, attempts to demonstrate an important role for NPY in the control of food intake using NPY knockout mice, NPY antisense oligodeoxynucleotides and anti-NPY antibodies has produced equivocal results. Despite this many pharmaceutical companies have moved ahead with the search for agonists and antagonists of NPY receptor subtypes as antiobesity agents. Antagonists of the NPY Y1 and NPY Y5 receptor subtype initially looked promising since analogs of NPY with high selectivity for these receptors strongly stimulated food intake. However, attempts to inhibit the signaling of NPY through the NPY Y1 and NPY Y5 receptors has produced equivocal effects on food intake. Recent observations that the gut derived peptide PYY3-36 suppresses appetite by stimulating both peripherally and centrally located NPY Y2 receptors remain controversial in animals but the effects look promising in human studies. Whether this will be the long awaited therapy based on manipulation of NPY receptors will await further studies of long term efficacy and more importantly a favorable side effect profile.