Losing 5-25% body weight can decrease onset and mortality from diseases including type-2-diabetes. Current obesity treatments focus on reducing calorie-intake through diet, surgery or drugs; however, these approaches are often ineffective long-term or have significant side effects. More than 65% of Australian adults remain overweight or obese, underscoring the need for new approaches. Exercise is a cornerstone weight loss strategy; however, few patients can achieve long-lasting weight loss with exercise alone. Mitochondrial uncoupling is an alternative mechanism to increase energy expenditure through decreasing caloric efficiency at the inner mitochondrial membrane. In this talk I will discuss efforts to target energy expenditure with uncouplers, and our studies investigating if the metabolic and weight loss benefits of exercise can be enhanced by combination treatment with BAM15, a mitochondria-selective mitochondrial uncoupler.