Major intracellular buffers are phosphates and proteins, such as hemoglobin. The hydrogen ion concentration of extracellular fluid is also closely regulated.

Carbon dioxide generated through the metabolism yields hydrogen ions through conversion to carbonic acid. However, generally, there is no net physiological gain because the reverse process occurs with passage of blood through the lungs.

Sodium bicarbonate and carbonic acid constitute the most important buffer in the extracellular space. If the kidneys did not reabsorb the large amount of filtered bicarbonate, the body would become very acidic. Hydrogen ion excretion and bicarbonate reabsorption are the two primary mechanisms for the homeostatic regulation of physiological pH.