The finding that hypoxic/ischemic injury leads to plasma membrane bleb formation provided the first evidence that the plasma membrane may serve as a site of expression of hypoxic/ischemic injury. Subsequent studies have focused on the mechanisms by which hypoxic/ischemic injury leads to plasma membrane damage. Numerous studies have demonstrated an association between alterations in plasma membrane phospholipid metabolism and myocardial, renal and hepatic hypoxic/ischemic injury, documented as a temporal correlation between phospholipid degradation and loss of cell viability. Structural and topographical alterations in plasma membrane phospholipid organization and order during hypoxic/ischemic injury have also been observed. Improved survival of hypoxic/ischemic cells and tissues in the presence of phospholipase inhibitors, anti-phospholipase antibodies and acidic intracellular pH (pH.), has been taken as evidence of the involvement of pH-dependent phospholipases in hypoxic/ischemic injury. The recent discovery that: (1) A calcium-independent phospholipase A2 selectively hydrolyzes the plasmalogen molecular species in ischemic myocardium sarcolemma, (2) Hypoxic/ischemic injury in hepatocytes leads to the expression of a group II 14 kDa phospholipase A2, (3 ) Incubation of hepatocytes with antisense oligonucleotides directed against a group II14 KDa phospholipase A2 protects cells against hypoxic injury, and (4) acidotic pH protects cells against hypoxic injury and inhibits phospholipase A2 activity, suggests that pH-dependent phospholipase A2 activity is a critical regulator of hypoxic/ischemic injury.