Inspiratory muscles are uniquely adapted for endurance, but their function is compromised in chronic obstructive pulmonary disease (COPD) due to increased loads, reduced mechanical advantage, and increased ventilatory requirements. The hyperinflation of COPD reduces the flow and pressure-generating capacity of the diaphragm. This is compensated by a threefold increase in neural drive, adaptations of the chest wall and diaphragm shape to accommodate the increased volume, and adaptations of muscle fibers to preserve strength and increase endurance. Paradoxical indrawing of the lower costal margin during inspiration in severe COPD (Hoover's sign) correlates with high inspiratory drive and severe airflow obstruction rather than contraction of radially oriented diaphragm fibers. The inspiratory muscles remain highly resistant to fatigue in patients with COPD, and the ultimate development of ventilatory failure is associated with insufficient central drive. Sleep is associated with reduced respiratory drive and impairments of lung and chest wall function, which are exaggerated in COPD patients. Profound hypoxemia and hypercapnia can occur in rapid eye movement sleep and contribute to the development of cor pulmonale. Inspiratory muscles adapt to chronic loading with an increased proportion of slow, fatigue-resistant fiber types, increased oxidative capacity, and reduced fiber cross-sectional area, but the capacity of the diaphragm to increase ventilation in exercise is compromised in COPD. In COPD, neural drive to the diaphragm increases to near maximal levels in exercise, but it does not develop peripheral muscle fatigue. The improvement in exercise capacity and dyspnea following lung volume reduction surgery is associated with a substantial reduction in neural drive to the inspiratory muscles.