Functional loss (often quantified as exercise limitation) is common in patients with chronic lung disease. The factors involved are multiple and many may be present together in a given patient. Ventilatory factors involve an imbalance in load/capacity relationships. Specifically, breathing loads from abnormal respiratory-system mechanics and/or excessive ventilatory demand cannot be handled by respiratory muscles that are dysfunctional or malpositioned. Gas-exchange factors involve impaired ventilation-perfusion relationships that lead to hypoxemia, impaired oxygen delivery, and pulmonary hypertension. Cardiovascular factors involve coexisting intrinsic heart disease, right-ventricular overload from pulmonary vascular abnormalities, and simple deconditioning. Skeletal muscle (both respiratory and limb) factors involve direct inflammatory mediator effects on muscle function, malnutrition, blood-gas abnormalities, compromised oxygen delivery from right-heart dysfunction, electrolyte imbalances, drugs, and comorbid states. Other less well understood factors include excessive dyspnea, impaired motivation, orthopedic issues, and psychiatric issues.