A single bout of contractile activity produces a multitude of time- and intensity-dependent hormonal and cellular perturbations within skeletal muscle. With the onset of contractile activity, cytosolic and mitochondrial [Ca²⁺] levels are rapidly increased and, depending on the relative intensity of the exercise, metabolite concentrations change. These contraction-induced metabolic disturbances activate several key kinases and phosphatases involved in signal transduction. Chief among these are the calcium-dependent signalling pathways that respond to elevated Ca²⁺ concentrations (including Ca²⁺/calmodulin-dependent kinase [CaMK], Ca²⁺-dependent protein kinase C [PKC] and the Ca²⁺/calmodulin-dependent phosphatase calcineurin); the 5'-adenosine monophosphate-activated protein kinase (AMPK), several of the mitogen-activated protein kinases (MAPK), and protein kinase B/Akt. In addition, there are exercise-induced central nervous system (CNS) stimulatory effects on various hormones and endocrine organs that promote the oxidation of carbohydrate-based fuels. With repeated bouts of contractile activity (i.e. exercise training) there are numerous and coordinated biochemical adaptations in skeletal muscle that decrease the reliance on carbohydrate-based fuels and enhance the oxidation of lipid-based fuels via reduced sympathetic nervous system responses to any given submaximal exercise intensity. These adaptations serve to minimize cellular disturbances during subsequent exercise bouts. Accordingly, chronic adaptations in skeletal muscle are likely to be the result of the cumulative effects of repeated bouts of exercise, with the initial signaling responses leading to such adaptations occurring after each (acute) training session. This chapter will summarize our current understanding of the hormonal and cellular control of bioenergetics in human skeletal muscle.