Obesity and its associated metabolic and cardio-vascular disorders are among the most chal-lenging health problems confronting developed countries. Not only is obesity remarkably common, affecting more than one-third of US adults, and very challenging to treat, but it is also tightly linked to type 2 diabetes and related metabolic disorders. A major obstacle to effective obesity treatment is that lost weight tends to be regained over time (1). Although the mechanisms underlying recovery of lost weight are incompletely understood, a large literature suggests that body fat stores are subject to homeostatic regulation, and that this process occurs in obese as well as normal-weight individuals. From this perspective, obesity can be viewed as a disorder in which the biologically defended level of body fat mass is increased. Recent findings implicate inflammation in key hypothalamic areas for body weight control in this process. In this review, we present an overview of energy homeostasis—the biological process that underlies the control of body fat mass—and describe evidence that defects in this regulatory system contribute to obesity pathogenesis. We then address molecular characteristics of hypothalamic inflammation and their implications for obesity pathogenesis (detailed more extensively in refs. 2, 3), followed by evidence linking high-fat diet (HFD) feeding to neuropathological alteration of key hypothalamic areas controlling energy balance. We conclude by considering how cell-cell interactions may contribute to this deleterious hypothalamic response and the implications of these interactions for obesity pathogenesis.