The respiratory system provides a quick response to an acid-base imbalance through control of the partial pressure of carbon dioxide (PaCO₂) in the arterial blood. When levels are elevated, CO₂ is a potent stimulus for ventilation. Carried by the red blood cell, carbon dioxide readily diffuses across the blood-brain barrier, reacting with H₂O to form H₂CO₃, which in turn splits into HCO₃ and H⁺.

It is H⁺ that is responsible for stimulating the respiratory drive. Increased amounts of H⁺ cause an increase in respirations, and a decreased amount of H⁺ results in decreased respirations. As ventilation increases CO₂ is blown off, leaving a decreased amount of carbon dioxide available to bond with H₂O. If acid is required for balancing the pH, a decreased respiratory rate helps to retain CO₂.