THE PAST decade has witnessed an upsurge in our understanding of the hypothalamic regulation of appetite. Expression of appetite or the motivational drive toward an energy source is a highly regulated phenomenon in vertebrates. It is considered a cornerstone for maintenance of energy homeostasis and for rigidly guarding the body weight around a set point. Abnormalities in the onset, periodicity, duration, and magnitude of eating episodes generally underlie augmented appetite (1–3). Increased appetite, whether temporary, as seen clinically in transient bingeing, or permanent, invariably culminates in an increased rate of body weight gain and obesity (1, 4–6). On the other hand, anorexia due to psychobiological causes (7, 8) or in response to acute and chronic infections, inflammation, and trauma is followed by severe loss of body weight (9–11). There is now a growing recognition that expression of appetite is chemically coded in the hypothalamus (1, 12). A perceived corollary is that subtle and progressive derangement in this neurochemical signaling, produced by environmental, genetic, and hormonal factors, impels either hyperphagia or anorexia (1). This conceptual advance has led not only to the identification and characterization of a multitude of neurotransmitters/neuromodulators that either propagate and transmit, or terminate appetite-stimulating impulses, but also to the precise tracking of pathways containing these signal molecules and the intricate interconnections among them. Increased knowledge of the molecular events governing synthesis, release, and signal transduction sequelae of each of these appetite-regulating messengers has enhanced our awareness of the phenomenon of coexistence and corelease of these chemicals in the cross-talk that ensues in response to an ever changing internal milieu (1). Consequently, information amassed during this decade has revised our views on the hypothalamic control of appetite and helped to detail the mechanistic attributes of locally derived signals in regulating energy homeostasis. These attributes have crystallized into the following broad categories: 1) Embedded in the networks controlling a multitude of hypothalamic functions (1, 13, 14), there is a distinct circuitry regulating appetite. This circuitry is composed of an interconnected network of pathways elaborating and emitting orexigenic and anorexigenic signals (1, 15). 2) The neurons producing these orexigenic and anorexigenic signal molecules are subject to modulation by the internal milieu comprised of a variety of hormonal and other biologically active molecules. In this respect, the recent identification of the adipocyte protein, leptin, has renewed interest in feedback