Cardiopulmonary bypass (CPB) is associated with a metabolic acidosis of variable severity. The etiology and pathogenesis of such acidosis have eluded full understanding for many years. Such acidosis has often been ascribed to splanchnic ischemia. Splanchnic ischemia would release metabolic acid (especially lactate) into the systemic circulation with accompanying metabolic acidosis. However, there has never been any convincing demonstration of hyperlactatemia in the vast majority of patients undergoing CPB, if a lactate-free pump prime is used. Nonetheless, all patients still experience the development of metabolic acidosis during CPB. Furthermore, sampling of the splanchnic effluent (hepatic vein blood) has not been performed to confirm the postulated acid release from the splanchnic circulation. Finally, all previous analyses of acid-base changes during CPB have not included quantitative biophysical principles. More recently, however, we have applied such principles to the analysis of the metabolic acidosis of CPB and to the measurement of trans-splanchnic acid-base changes. Our findings demonstrate that, in stable patients undergoing CPB, metabolic acidosis is iatrogenic in nature and results from the administration of pump primes with a chloride concentration greater than the normal plasma chloride concentration. Such excess chloride results in a decreased strong ion difference, which, in turn, increases the dissociation of plasma water, thus liberating hydrogen ions whose activity lowers blood pH. The splanchnic circulation, on the other hand, makes no discernible contribution to such metabolic acidosis.