The increasing prevalence of obesity and its comorbidities reflects the interaction of genes that favor the storage of excess energy as fat with an environment that provides ad libitum availability of energy-dense foods and encourages an increasingly sedentary lifestyle. Although weight reduction is difficult in and of itself, anyone who has ever lost weight will confirm that it is much harder to keep the weight off once it has been lost. The over 80% recidivism rate to preweight loss levels of body fatness after otherwise successful weight loss is due to the coordinate actions of metabolic, behavioral, neuroendocrine and autonomic responses designed to maintain body energy stores (fat) at a central nervous system-defined 'ideal'. This 'adaptive thermogenesis' creates the ideal situation for weight regain and is operant in both lean and obese individuals attempting to sustain reduced body weights. Much of this opposition to sustained weight loss is mediated by the adipocyte-derived hormone 'leptin'. The multiple systems regulating energy stores and opposing the maintenance of a reduced body weight illustrate that body energy stores in general and obesity in particular are actively 'defended' by interlocking bioenergetic and neurobiological physiologies. Important inferences can be drawn for therapeutic strategies by recognizing obesity as a disease in which the human body actively opposes the 'cure' over long periods of time beyond the initial resolution of symptomatology.