Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder characterized by dysfunction of the small and large airways, as well as by destruction of the lung parenchyma and vasculature, in highly variable combinations. Breathlessness and exercise intolerance are the most common symptoms in COPD and progress relentlessly as the disease advances. Exercise intolerance is multifactorial, but in more severe disease, ventilatory limitation is often the proximate exercise-limiting event. Multiple factors determine ventilatory limitation and include integrated abnormalities in ventilatory mechanics and ventilatory muscle function as well as increased ventilatory demands (as a result of gas exchange abnormalities) and alterations in the neuroregulatory control of breathing. Despite its heterogeneity, the pathophysiological hallmark of COPD is expiratory flow limitation. When ventilation increases in flow-limited patients during exercise, air trapping is inevitable and causes further dynamic lung hyperinflation (DH) above the already increased resting volumes. DH causes elastic and inspiratory threshold loading of inspiratory muscles already burdened with increased resistive work. It seriously constrains tidal volume expansion during exercise. DH compromises the ability of the inspiratory muscles to generate pressure, and the positive intrathoracic pressures likely contribute to cardiac impairment during exercise. Progressive DH hastens the development of critical ventilatory constraints that limit exercise and, by causing serious neuromechanical uncoupling, contributes importantly to the quality and intensity of breathlessness. The corollary of this is that therapeutic interventions that reduce operational lung volumes during exercise, by improving lung emptying or by reducing ventilatory demand (which delays the rate of DH), result in clinically meaningful improvement of exercise endurance and symptoms in disabled COPD patients.