Understanding the metabolic factors that contribute to obesity development and weight loss success are critical for combating obesity and obesity‐related disorders. This review provides an overview of energy metabolism with a particular focus on mitochondrial function in health and in obesity. Mitochondrial proton leak contributes significantly to whole body energy expenditure and the potential role of energy uncoupling in weight loss success is discussed. We provide evidence to support the hypothesis that differences in energy efficiency are important regulators of body weight and weight loss success.