Acid–base homeostasis is the homeostatic regulation of the pH of the body's extracellular fluid (ECF). The proper balance between the acids and bases (i.e. the pH) in the ECF is crucial for the normal physiology of the body—and for cellular metabolism. The pH of the intracellular fluid and the extracellular fluid need to be maintained at a constant level.

The three dimensional structures of many extracellular proteins, such as the plasma proteins and membrane proteins of the body's cells, are very sensitive to the extracellular pH. Stringent mechanisms therefore exist to maintain the pH within very narrow limits. Outside the acceptable range of pH, proteins are denatured (i.e. their 3D structure is disrupted), causing enzymes and ion channels (among others) to malfunction.

An acid–base imbalance is known as acidemia when the pH is acidic, or alkalemia when the pH is alkaline.

In humans and many other animals, acid–base homeostasis is maintained by multiple mechanisms involved in three lines of defense:

The second and third lines of defense operate by making changes to the buffers, each of which consists of two components: a weak acid and its conjugate base. It is the ratio concentration of the weak acid to its conjugate base that determines the pH of the solution. Thus, by manipulating firstly the concentration of the weak acid, and secondly that of its conjugate base, the pH of the extracellular fluid (ECF) can be adjusted very accurately to the correct value. The bicarbonate buffer, consisting of a mixture of carbonic acid (H₂CO₃) and a bicarbonate (HCO⁻
₃) salt in solution, is the most abundant buffer in the extracellular fluid, and it is also the buffer whose acid-to-base ratio can be changed very easily and rapidly.

The pH of the extracellular fluid, including the blood plasma, is normally tightly regulated between 7.32 and 7.42 by the chemical buffers, the respiratory system, and the renal system. The normal pH in the fetus differs from that in the adult. In the fetus, the pH in the umbilical vein pH is normally 7.25 to 7.45 and that in the umbilical artery is normally 7.18 to 7.38.

Aqueous buffer solutions will react with strong acids or strong bases by absorbing excess H⁺
ions, or OH⁻
ions, replacing the strong acids and bases with weak acids and weak bases. This has the effect of damping the effect of pH changes, or reducing the pH change that would otherwise have occurred. But buffers cannot correct abnormal pH levels in a solution, be that solution in a test tube or in the extracellular fluid. Buffers typically consist of a pair of compounds in solution, one of which is a weak acid and the other a weak base. The most abundant buffer in the ECF consists of a solution of carbonic acid (H₂CO₃), and the bicarbonate (HCO⁻
₃) salt of, usually, sodium (Na⁺). Thus, when there is an excess of OH⁻
ions in the solution carbonic acid partially neutralizes them by forming H₂O and bicarbonate (HCO⁻
₃) ions. Similarly an excess of H⁺ ions is partially neutralized by the bicarbonate component of the buffer solution to form carbonic acid (H₂CO₃), which, because it is a weak acid, remains largely in the undissociated form, releasing far fewer H⁺ ions into the solution than the original strong acid would have done.

The pH of a buffer solution depends solely on the ratio of the molar concentrations of the weak acid to the weak base. The higher the concentration of the weak acid in the solution (compared to the weak base) the lower the resulting pH of the solution. Similarly, if the weak base predominates the higher the resulting pH.^{[citation needed]}