Overweight and obesity are increasing in prevalence, and this has resulted in a significant public health burden. Therefore, it is important to identify interventions that prevent weight gain and prevent weight regain after weight loss. Energy expended in physical activity has the potential to affect energy balance, and this can potentially affect body weight regulation. There is some evidence that physical activity can minimize weight gain, and it appears that needs to be moderate to vigorous in intensity to significantly affect body weight. Moreover, it appears that improvements in fitness are associated with reductions in risk of weight gain. Physical activity also is associated with improved maintenance of weight loss. Although it appears that interventions targeting physical activity are necessary to affect weight gain and improve long-term weight loss, the impact of these interventions on other components of energy balance should be examined. In addition, although minimal public health recommendations can significantly affect health outcomes, additional research is needed to identify the optimal dose of physical activity to prevent weight gain and improve long-term weight loss.