The aetiology and treatment of obesity have been fraught with disappointment for researchers, because the mechanisms that control fuel homeostasis and adiposity are incompletely understood. It is assumed that regulatory processes match the dietary fuel supply with energy requirements in order to maintain a stable body mass and adiposity. In this context several theories have been proposed to explain the laws of thermodynamics describing the conservation and transformation of energy in living organisms. In the light of new evidence it can now be hypothesized that the control of body weight and composition depends on an axis with three interrelated and self-controlled components: (1) food intake; (2) nutrient turnover and thermogenesis; (3) body fat stores. Complex feedback mechanisms underlie all these components. The major factors involved in obesity seem to be dietary and physical activity habits. These factors are affected by susceptibility genes that in turn may influence energy expenditure, fuel metabolism, muscle fibre function and appetite or food preferences. However, the increasing rates of obesity cannot be explained exclusively by changes in the gene pool, although genetic variants that were previously ‘silent’ are now being triggered by the high availability of energy- and fat-dense foods, and by the increasingly sedentary lifestyle of modern societies. The study of factors such as genetics and lifestyle implicated in weight gain and obesity is crucial for predictions about the future impact of the global epidemic of obesity, and provides a unique opportunity for the implementation of preventive action.