We briefly review the evidence for a hypothesis, which links the ventilatory response to heavy intensity, sustained exercise-to-exercise performance limitation in health. A key step in this linkage is a respiratory muscle fatigue-induced metaboreflex, which increases sympathetic vasoconstrictor outflow, causing reduced blood flow to locomotor muscles and locomotor muscle fatigue. In turn, the limb fatigue comprises an important dual contribution to both peripheral and central fatigue mechanisms, which contribute to limiting exercise performance. Clinical implications for respiratory limitations to exercise in patients with chronic obstructive lung disease (COPD) and chronic heart failure (CHF) are discussed and key unresolved problems are outlined.