Buffers absorb excess acid (H⁺) or excess base (OH⁻) without a significant change in pH. They work as pairs, each containing a weak acid and a weak base. The carbonic acid-bicarbonate buffer system is the most important extracellular buffer system. Hemoglobin is an important buffer in erythrocytes. Phosphorus and protein are the primary intracellular buffers. Most buffer systems disassociate rapidly in response to changes in pH. The carbonic acid-bicarbonate buffer system acts in both the lungs and the kidneys. As the PaCO₂ increases in the blood, more carbonic acid is formed. The lungs compensate for this by blowing off CO₂, and the kidneys compensate by either reabsorbing bicarbonate or producing more. The respiratory response
begins within minutes or hours. The renal response occurs within hours or days. Conversely, if the ratio between bicarbonate (HCO₃) and carbonic acid (H₂CO₃) shifts toward the basic side, H⁺ is conserved or produced by the kidneys and the lungs retain CO₂ (allowing more carbonic acid to be formed). The lungs respond similarly to changes in nonvolatile acid levels, which compensates for it. This response takes a little longer. When the body is adequately compensating for changes in pH, the pH of the blood is normal but there are variations in the levels of HCO₃ or PaCO₂ and other blood chemistry values. This compensation may also be reflected in changes in respiratory rate and depth and pH of the urine. The elderly respond less quickly to changes in pH.

Proteins carry negative charges and are buffers for H⁺. Hemoglobin is an excellent intracellular buffer because it binds readily with H⁺ and CO₂. In addition, the kidney regulates amounts of PO₄ and ammonia in response to changes in the pH of the blood, which allows H⁺ to be excreted in the urine. These systems work in conjunction with the H⁺ ion and bicarbonate renal mechanisms previously described to effect a normal pH and maintain homeostasis. Shifts in K⁺ and H⁺ ions in acidosis or alkalosis also assist in buffering. In acidosis, H⁺ cannot be excreted without another cation being retained. Because K⁺ is the ion retained, hyperkalemia develops in acidosis. Additionally, when excess H⁺ moves into the cell, K⁺ leaves, further contributing to hyperkalemia. The reverse happens with alkalosis, resulting in hypokalemia. Ca⁺⁺ is also affected by serum pH. More Ca⁺⁺ is bound with serum proteins in an alkalotic state; therefore hypocalcemia accompanies alkalosis, and hypercalcemia accompanies acidosis.