Physical inactivity (or muscle disuse) offers a useful laboratory intervention to study the role of muscle contraction in the regulation of skeletal muscle mass and quality. Physical inactivity interventions, such as limb immobilisation or bed-rest, also offer appropriate strategies to study muscle loss and deconditioning in the context of clinical situations such as injury, illness or hospitalisation. Such experimental physical inactivity experiments are commonly carried out in healthy, uninjured volunteers over relatively short periods (1 to 14 days). These ‘uncomplicated’ disuse models have shown us that the withdrawal of contraction per se brings about rapid declines in muscle mass and quality. Mechanistically, such work has shown declines in postabsorptive muscle protein synthesis rates and the development of anabolic resistance to dietary protein likely drive this muscle deconditioning, given human experiments have thus far failed to show changes in muscle protein breakdown. Interestingly, disuse studies encompassing complicating factors that may be beyond only withdrawal of muscle contraction, such as impact on nutritional requirements, presence of muscle damage, inflammation or stress related responses, give a less clear mechanistic picture. This lecture will review the contemporary evidence base for the physiological regulation of skeletal muscle mass during disuse, drawing on data from human studies applying both uncomplicated and more complicated experimental models.