Physical exercise is a stress to the human body, which evokes physiological changes to accommodate to the stressor. One of the most reactive physiological systems to stress exposure is the neuroendocrine. During acute exercise, the sympathetic nervous system and hormones of the endocrine system respond rapidly and dramatically, principally to: (a) induce cardiovascular-respiratory adjustments, (b) activate energy production pathways and mobilize energy substrates, and (c) facilitate maintenance of adequate hydration—thermoregulation. Chronic exposure to exercise (i.e., training) induces accommodations in the neuroendocrine system to allow exercise adjustments to occur but does so with a less robust nervous/hormonal response as part of training adaptations (in part due to target tissue improved sensitivity). Metabolically exercise places great demands on the ability to utilize and in turn produce energy (adenosine triphosphate; ATP) within skeletal muscle via a variety of biochemical pathways. Which pathways are utilized and predominant are a function of the intensity of the exercise performed and the duration for which it is carried out. Put simply, whether the energy use/generation is primarily dependent on the stored ATP sources or, anaerobic- versus aerobic-dependent biochemical pathways. Furthermore, muscular energy production and utilization show tremendous capacity for improvement and adaptation when exercise training regimes are efficacious. This chapter presents an overview of the fundamentals of these physiological events.