Despite a global obesity epidemic suggesting that human physiology is unable to prevent unhealthy gains in body weight, ample evidence indicates that weight can be tightly regulated. Food intake regulation is complex and in this article we will present a basic endocrine feedback loop model of energy homeostasis. Next, integration of long-term regulation with short-term, meal specific regulation and satiety will be discussed. Finally, the role of adiposity signals in modulation of food reward will be highlighted. A basic understanding of the structure-function of these systems will inform the challenges of clinical care for those with disorders of energy balance.