Chronic obstructive pulmonary disease (COPD) affects millions of people worldwide and is predicted to become the fourth leading cause of death by 2030. The importance of systemic effects of the disease is increasingly recognized, in particular loss of skeletal muscle bulk and skeletal muscle weakness. Both fat-free mass depletion and skeletal muscle weakness are predictors of mortality in COPD and also impact exercise capacity and quality of life. Potential mechanisms of muscle weakness include systemic factors such as inflammation and hypoxia, as well as local factors such as patterns of muscle loading and disuse. Genetic factors also likely influence susceptibility. Currently, exercise is the best way of reversing muscle weakness when delivered as part of a pulmonary rehabilitation program. There is an association between loss of skeletal muscle and COPD exacerbations, so strategies to prevent exacerbations or attenuate muscle wasting in this context are needed. Other therapeutic options, which have been investigated, include repetitive electrical stimulation of the quadriceps muscle as an adjunctive therapy to exercise, nutritional supplementation, testosterone replacement in men, and growth hormone, but there is limited evidence of benefit at this time. Further research is required to clarify causative factors and investigate other potential therapeutic options.