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Chronic obstructive pulmonary disease (COPD) is now well recognized as a systemic disorder. Apart from the lungs, the musculoskeletal system is one of the most frequently affected organs. Skeletal muscle dysfunction contributes independently to symptoms, impaired health status, increased health care resource usage, and reduced survival. Pulmonary impairment is largely irreversible and therefore the skeletal muscles represent a potential site to improve functioning and symptoms in patients with COPD. The etiology of skeletal muscle dysfunction in COPD is probably multifactorial with varying contributions from physical inactivity, systemic inflammation, hormone imbalance, tissue hypoxia, nutritional abnormalities, oxidative stress, genetic susceptibility, and chronic corticosteroid use. Exercise training is effective at reversing skeletal muscle dysfunction, and pulmonary rehabilitation, a largely exercise-based intervention, has become a cornerstone in the management of COPD. This article summarizes the structural and functional characteristics of skeletal muscle dysfunction in COPD, reviews the possible contributing factors, and describes the effect of pulmonary rehabilitation on skeletal muscle structure and function.