In health, the near-eucapnic, highly efficient hyperpnea during mild-to-moderate intensity exercise is driven by three obligatory contributions, namely, feedforward central command from supra-medullary locomotor centers, feedback from limb muscle afferents, and respiratory CO2 exchange (V̇CO2). Inhibiting each of these stimuli during exercise elicits a reduction in hyperpnea even in the continuing presence of the other major stimuli. However, the relative contribution of each stimulus to the hyperpnea remains unknown as does the means by which V̇CO2 is sensed. Mediation of the hyperventilatory response to exercise in health is attributed to the multiple feedback and feedforward stimuli resulting from muscle fatigue. In patients with COPD, diaphragm EMG amplitude and its relation to ventilatory output are used to decipher mechanisms underlying the patients' abnormal ventilatory responses, dynamic lung hyperinflation and dyspnea during exercise. Key contributions to these exercise-limiting responses across the spectrum of COPD severity include high dead space ventilation, an excessive neural drive to breathe and highly fatigable limb muscles, together with mechanical constraints on ventilation. Major controversies concerning control of exercise hyperpnea are discussed along with the need for innovative research to uncover the link of metabolism to breathing in health and disease.