Neuropeptide Y (NPY), the most abundant peptide present in the mammalian brain, exhibits a wide spectrum of central and peripheral activities mediated by at least six G-protein coupled receptors. The latter observation, and the implication of NPY in the pathophysiology of feeding, seizures, diabetes, intestinal dysfunction, cardiovascular diseases and respiratory disorders, have led to vigorous efforts to dissociate various effects of NPY and develop receptor selective ligands required for fundamental investigations, and possible clinical utility. These efforts have made significant advancement in the development of antagonists, especially for Y(1) and Y(5) receptors mediating NPY effects on feeding and/or thermogenesis. However, only a limited progress has been made in the case of Y(2) ligands, and none in the case of Y(4) ligands. Moreover, most of the nonpeptidic ligands developed to date have little use clinically because of their solubility and toxicity problems and their limited passage through blood-brain barrier. Furthermore, no progress has been made in developing lower molecular weight agonists, which may also have clinical potential in treating seizures, intestinal dysfunction, respiratory disorders, cachexia and anorexia. Thus, despite significant advances, NPY research is expected to attract scientists for years to come in the pursuit to develop clinically useful ligands. The recent advances in the peptide drug delivery techniques have given added impetus for these efforts. This article reviews the usefulness of widely used ligands as well as those developed more recently.