The epidemic emergence of modern chronic diseases largely stems from the adoption of a sedentary lifestyle and excess energy intake. However, it has long been known that regular physical activity induces multiple adaptations within skeletal muscle and other organs and these adaptations have positive outcomes for the prevention and treatment of many metabolic disorders. In recognition of such benefits, a recent goal of industry-funded research is to discover orally active compounds that mimic the effects of exercise training, so-called “exercise pills”. This article provides an overview of the role of skeletal muscle in health and disease and discusses whether “exercise mimetics” have any potential to combat metabolic diseases.