The hypothalamus, long known to play a determinant role in food intake and satiety, has recently been shown to exert this homeostatic function via peptidergic neuronal circuits. The major peptide that has been identified as orexigenic, namely neuropeptide Y (NPY), is suppressed by leptin, an adipocyte-derived hormone, in a potential circuit that seems to function as an adipostat. Information regarding energy balance is fed back to the paraventricular nucleus of the hypothalamus where a complex interplay between thyrotropin-releasing hormone (TRH) and corticotrophin-releasing hormone (CRH) determines consequent effects in thermogenesis and stress reactions. Inflammatory mediators that have been implicated in anorexia simultaneously suppress TRH in a dominant way that overcomes the feedback effects of the thyroid hormones. Moreover, endogenous opioids and melanotropic peptides modulate orexigenic and thermogenic effects in a complex, yet poorly understood, way. However, TRH metabolism, which is affected by dietary modifications, seems to be involved in the orexigenic events that take place in the hypothalamus. It is, therefore, evident that TRH is directly involved in the complex hypothalamic networks that establish energy balance by modulation of food intake, satiety, thermogenesis, and other autonomic responses.