Gas exchange and the correlated changes in blood and tissue metabolic and acid-base status were investigated during long term exposure of the toad Bufo marinus to graded levels of hypoxia. During hypoxia, P CO 2 values in blood and tissues fell, leading to a transient alkalosis in the extracellular but not in the intracellular space. A reduction in blood perfusion of the skin during hypoxia may explain why P CO 2 was low in sartorius muscle under normoxia, but approached the P CO 2 values found in other tissues (gastrocnemius muscle, ventricle) under hypoxia. At P O 2 values below the critical P O 2 , lactate was formed and the decrease in total CO 2 was accelerated. Lactate levels in the plasma were higher than in the intracellular space of the skeletal muscles, a finding attributed to the pH-dependent distribution of lactic acid across the cell membrane. The comparison of metabolic proton quantities with those found in the extra- and intracellular acid-base status suggests that CO 2 release was accelerated by anaerobic proton formation. The alkalizing effect of decreasing P CO 2 in the skeletal musculature was compensated for by a release of base equivalents into the blood. The resulting alkalosis in the blood was probably compensated for by the release of base equivalents into the environment.