A significant percentage of the population is classified as obese, and there is a growing need to develop novel therapy to reduce body weight. It has long been appreciated that caloric restriction and exercise are the cornerstones of any weight loss method. This review outlines the challenges faced when attempting to achieve weight loss and the metabolic adaptations that ensue upon reductions in body weight which make sustaining weight loss extremely difficult. We discuss the need for novel approaches to weight loss that would increase basal metabolic rate and counter the biological adaptations that provide barriers for maintaining weight reduction. We introduce two metabolic processes, hypobaric hypoxia and cold exposure, which, when activated, cause increased metabolic rate even in the presence of reduced caloric intake. While we do not suggest that these are long-term viable options for methods to achieve weight loss, we are introducing these as pathways that may be targeted to eventually develop novel therapies to achieve sustainable weight loss.