Muscle was one of the first tissues in which substantial phenotypic adaptation of fully differentiated adult cells was demonstrated. The control of gene expression, and therefore the nature of the proteome, is under the control of external influences, including hormonal signals, but most remarkably, allows the muscle fibre to adapt to the accustomed pattern of activity. When that pattern of activity changes in terms of daily amount or pattern, the muscle fibres change to accommodate the required activity. If daily activity increases, then the mechanisms of sustained energy supply are enhanced, and one can identify an ‘endurance’ phenotype. If only short bursts of activity are required relatively infrequently, the fibres tend to become fast and powerful, taking on a ‘sprint’ phenotype. The intracellular mechanisms that tend to match the phenotype with the required activity are multifaceted. A period of painstaking mechanistic analyses during the past decades can now be re-evaluated with much more comprehensive analyses based on the dynamic changes in the transcriptome, epigenome and proteome. Such adaptation is an important component of athletic training for power or endurance events, the problematic loss of muscle with ageing, forced bedrest, or cachexia, and the healthy control of blood glucose in feeding, fasting and exercise. This chapter reviews the historical evidence, focusing on the progressive improvement in the experimental models available to probe this remarkable aspect of neuromuscular physiology.