Neuropeptides are essential for the regulation of appetite and body weight within the hypothalamus. The understanding of the neuropeptide regulation of energy homeostasis has been greatly advanced by the recent discovery of leptin, the protein product of the obese gene (ob). Significant new insights into the relationship between peripheral adiposity signals and their impact on the hypothalamic neuropeptide signaling circuitry have provided some crucial missing links in the negative-feedback regulation of appetite and body weight. The neuropeptide Y orexigenic network is a final common pathway for this signaling cascade and, along with feeding-inhibitory neuropeptides such as melanocortin, corticotropin-releasing factor and glucagon-like peptide 1, it is a major target through which leptin exerts a regulatory tonic restraint on body adiposity.