An advanced understanding of acid-base physiology is central to the practice of critical care medicine. Intensivists spend much of their time managing problems that are related to fluids, electrolytes, and blood pH. Recent advances in the understanding of acid-base physiology occurred as the result of the application of basic physical-chemical principles of aqueous solutions to blood plasma. This analysis revealed three independent variables that regulate pH in blood plasma: carbon dioxide, relative electrolyte concentrations, and total weak acid concentrations. All changes in blood pH, in health and in disease, occur through changes in these three variables. This article reviews the physical-chemical approach to acid-base balance and considers clinical implications for these findings.