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Exercise has a powerful action on metabolism, and adaptation of the body to changes induced by exercise is fundamental to be able to provide the energy required for muscle contraction and physiological functions of vital tissues. Depending on the intensity and duration of exercise, different mechanisms are called on to make energy available, and under homeostatic control, this is guaranteed by rapid and coordinated changes in the secretion of several hormones. Molecular mechanisms controlling muscle function and fiber phenotype are related to the specific mode of muscle activation. We can distinguish between two fundamental types of physical activity, endurance exercise and strength exercise, although there is a continuum between these exercise modalities. Besides the acute changes induced by a single exercise session, regular exercise may induce chronic adaptations, improving exercise capacity and affecting energy metabolism. Notably, although acute metabolic effects of exercise are mostly due to insulin-independent effects, exercise training may improve muscle insulin sensitivity and is considered a key tool in the prevention and treatment of metabolic disorders. This chapter focuses on the biochemistry of energy supply to the exercising muscle, on molecular mechanisms involved and on the physiology of energy metabolism during exercise in healthy subjects and patients with insulin resistance and/or diabetes., (© 2016 S. Karger AG, Basel.)