This paper examines the role of energy expenditure, especially physical activity related energy expenditure, in the metabolic aspects of body weight regulation. New data have emerged from studies conducted over the last decade, demonstrating that physical activity is a critical factor contributing to successful body weight regulation in lean and obese individuals. A growing number of prospective studies show the protective role of increased physical activity against weight gain over time. Also, individuals who are successful in long-term maintenance of a weight reduction are highly likely to also be physically active. Participation in physical activity is among the best predictors of success in weight maintenance. Physical activity facilitates weight maintenance through direct energy expenditure and improved physical fitness. The latter facilitates the amount and intensity of daily activities. Both components are of importance in relation to energy and substrate balance. Exercise may act as a substitute for an enlarged fat mass, in bringing about rates of fat oxidation commensurate with fat intake. Metabolic effects on lipid mobilization and oxidation and morphological/biochemical changes in the muscle fiber, contribute to this successful regulation of body weight. A limited number of studies indicate that, the minimal level of additional energy expenditure by physical exercise required for protection against gain in excessive body fatness, is around 12 kcal/kg body weight/d. In conclusion, the amount of energy expended in physical activity, mediated by several metabolic factors, may play an important role in body weight regulation.