A decline in daily physical activity levels is clearly a major factor contributing to the current obesity epidemic affecting both developed and developing countries in the world. This escalating problem is associated with increased morbidity and mortality and reduced psychosocial health. Thus, increasing physical activity has become the strategy of choice in public health strategies to prevent obesity. Efforts to improve levels of physical activity in the population rely upon an accurate understanding of the determinants of physical activity. Most research has focused on environmental and social influences, while the potential for physical activity to be controlled by intrinsic biological processes has been largely overlooked. This review presents some of the compelling and diverse evidence that has emerged recently showing that physical activity energy expenditure is a critical factor in both the successful regulation of energy balance in normal individuals, as well as the abnormal regulation of energy balance that characterizes obesity. Although the metabolic and genetic factors involved in these regulatory processes remain mostly unidentified, some novel discoveries have been made in this area recently and these are described within this review.