The influence of hypoxemia upon the energy metabolism of the brain was studied by measuring the tissue concentrations of phosphocreatine, ATP, ADP, AMP, inorganic P, lactate, pyruvate, α-ketoglutarate, glutamate, and ammonia in the brains of rats after a 30 min reduction in the paO2 to minimally 15 mm Hg. Intracellular lactate and pyruvate concentrations were derived after correction for the lactate and pyruvate contained in the blood and extracellular fluid volumes of the tissue. When the pO2 was reduced below about 50 mm Hg, there were progressive increases in the intracellular lactate concentrations, and in the lactate/pyruvate ratios. At pO2's of about 35 mm Hg, the phosphocreatine content was reduced, but there were no significant changes in ATP, ADP, or AMP until the pO2 was reduced below 25 mm Hg. At these low pO2's the metabolic changes were exaggerated by even small decreases in the blood pressure.