Over the past decade, there has been a tremendous increase in the understanding of the molecular and neural mechanisms that control food intake and body weight. Yet, eating disorders and cachexia are still common and obesity cases are rising at alarming rates. Thus, despite recent progress, an increased understanding of the molecular and neural substrates that control body weight homeostasis is a major public health goal. In this review, we discuss the mechanisms by which metabolic signals interact with key behavioral, neuroendocrine and autonomic regulatory regions of the central nervous system (CNS). Additionally, we offer a model in which hormones such as leptin and ghrelin interact with similar CNS circuits and engage them in such a way as to maintain an appropriate and tight regulation of body weight and food intake. Our model predicts that over- or under-stimulation of these central pathways can result in the obesity, anorexia or cachexia.