A wide variety of toxic chemicals cause blebbing of the plasma membrane in isolated hepatocytes. These alterations in surface structure occur well before cell death. The formation of blebs appears to be directly related to changes in the concentration of extramitochondrial calcium ions. These changes probably reduce the ability of the hepatocyte cytoskeleton to maintain normal surface morphology. The concentration of soluble thiols, notably glutathione, appears to regulate the size of the extramitochondrial calcium ion pool. Disturbances in intracellular thiol and calcium ion homeostasis therefore seem to be responsible for the surface blebbing observed during toxic injury to isolated hepatocytes.