Arterial plasma pH (pHe) of unrestrained Sprague-Dawley rats was altered either by inhalation of different CO2 concentrations or infusion of sodium bicarbonate and then kept constant for two hours at the altered level. The intracellular pH (pHi) was then determined by application of the DMO-method in heart, brain, liver, spleen and ten different skeletal muscle groups. pHi varied linearly with the pHe in heart, brain, liver and spleen. pHi in skeletal muscle remained constant over a pHe range from 7.1-7.45 but varied linearly with pHe outside this range. The following facts were observed: pHi is influenced by CO2 or sodium bicarbonate; pHi varies in different tissues at specified pHe; skeletal muscle is well protected against slight acidosis because pHi remains constant; during metabolic and respiratory changes of pH quantitatively and qualitatively different bicarbonate exchanges occur in the plateau range of skeletal muscle; slight changes of pHe affect pHi in the heart, brain, liver, and spleen, and hence even small disturbances should be treated appropriately; therefore amount of buffer substances required for the correction of the overall acid-base status of the organism cannot be predetermined accurately from blood pH measurements. Frequent determinations of blood acid-base status are necessary to avoid misestimations of the therapeutical dosage of buffer substances. it is not necessary that a therapeutically applied buffer substance penetrates into the intracellular space. Generation or consumption of bicarbonate in the extracellular space is followed by bicarbonate exchange between both body compartments which will restore normal acid-base equilibrium.