Lifestyle intervention programs encompassing exercise and healthy diets are an option for the treatment and management of obesity and type 2 diabetes and have long been known to exert beneficial effects on whole-body metabolism, in particular leading to enhanced insulin-sensitivity. Obesity is associated with increased risk of several illnesses and premature mortality. However, physical inactivity is itself associated with a number of similar risks, independent of body-mass index, and is an independent risk factor for more than 25 chronic diseases, including type 2 diabetes and cardiovascular disease. This article addresses the debate regarding the relative effects of physical exercise itself and the effect of exercise-induced weight loss.