Sedentary lifestyles, limited physical exercise, and prolonged inactivity undoubtedly increase chronic diseases, including obesity, type 2 diabetes, and cardiovascular diseases. It is widely acknowledged that exercise induces a number of physiological adaptations that have beneficial effects in the prevention and treatment of these chronic metabolic diseases. Unfortunately, exercise compliance is extremely low and often not possible. The development of exercise science and molecular techniques has increased our understanding of the molecular pathways responsive to exercise. Knowledge of these molecular targets has led to the development of chemical interventions that can mimic the beneficial effects of exercise without requiring actual muscle activity. This review focuses on the concept of ‘exercise pills' and how they mimic the effects produced by physical exercise including oxidative fiber-type transformation, mitochondrial biogenesis, increased fat oxidation, angiogenesis, and improvement of exercise capacity. We also review candidate exercise pills, and contrast the beneficial effects and molecular mechanisms between physical exercise and exercise pills.