Although organisms normally regulate energy intake and expenditure in a precise manner, certain disease states, such as cancer, may disrupt this regulatory balance resulting in anorexia (reduced energy intake) in the presence of elevated metabolic rate. The search for mediators of this dysfunction has focused upon neuropeptides localized primarily in the hypothalamus and known to be potent regulators of feeding in normal circumstances. Of the compounds known to stimulate feeding in normal animals, dysfunction of neuropeptide Y (NPY) has been the focus of much research in experimental cancer anorexia studies. These experiments have shown NPY-induced feeding to be refractory in tumorbearing (TB) rats, with continuous infusion or repeated injections not reversing the anorexia. The release of NPY in the hypothalamus is also decreased in TB rats shortly after the development of anorexia. Although whole hypothalamic concentration of NPY is decreased prior to the onset of anorexia, concentrations are elevated in the cell body containing arcuate (ARC) nucleus, but are decreased in the paraventricular (PVN) nerve terminal area as compared to pair-fed (PF) controls. NPY gene expression is also increased in the ARC-containing ventromedial hypothalamus of TB and PF rats, but NPY mRNA was not increased in the PVN-containing dorsomedial area. Many of the changes in NPY level and gene expression may be secondary to decreased leptin and insulin in anorectic TB rats. NPY receptor binding is also altered in TB rats, with decreased affinity occurring prior to the onset of anorexia. Several anorexia-producing neuropeptides appear to interact with NPY in TB rats, which may down-regulate its normal control of feeding. Corticotropin releasing factor (CRF) is elevated in the hypothalamus of TB rats, and CRF has been shown to inhibit NPY-induced feeding. Another anorectic peptide of the melanocortin family, alpha-melanocyte stimulating hormone (α-MSH), decreases NPY-induced feeding and release. Since it appears that both CRF and a-MSH may be tonically-active, NPY may normally induce feeding through inhibiting these systems. In anorexia, the level of this tonic inhibition may be greater than can be overcome by NPY. Cytokines also appear to be involved in NPY dysfunction in cancer anorexia, with hypothalamic interleukin-1B (IL-1B) message being elevated in anorectic TB rats. In addition, IL-1B and NPY have mutual inhibitory effects on feeding. However, IL-1B did not affect NPY release from hypothalamus. Other possible circulating mediators of the anorexia in TB rats may be elevated ammonia, lactate and lipids as well as dysfunctional intracellular signal transduction. Therefore, it appears that NPY function is being inhibited by alterations in other neurochemicals, and simply administering NPY analogs may not reverse cancer anorexia.