© 2018 Weight regain after weight loss is one of the most significant challenges to successful obesity treatment. Regular exercise has long been touted as a strategy for weight loss maintenance, but the lack of clear evidence in clinical trials has caused some to question its effectiveness. In this review, we present the arguments both questioning and in support of exercise as an obesity therapeutic. Our purpose is to bring clarity to the literature, present a unified perspective, and identify the gaps in knowledge that need to be addressed in future studies. Critical questions remain including sex differences, individual variability and compensatory behaviors in response to exercise, exercise adherence, the role of energy flux and the molecular mechanisms mediating the beneficial effects of exercise after weight loss and during weight regain. Future research should focus on these critical questions to provide a more complete understanding of the potential benefits of exercise on weight loss maintenance.