Tissue responses to ischemia this Perspective series, ref. 4) carries a major energetic cost, and restoration of normal concentrations of key regulatory proteins may come too late to maintain the intracellular milieu in a manner consistent with survival. Events within ischemic cells also can target proteins for proteolytic destruction, and the accumulation of proteolytic fragments of certain proteins can have biological consequences (5). Damage to cell membranes, in addition to proteins, may preclude functional recovery. Calcium overload can impair recovery of mitochondrial function and can produce ischemic contractures with ensuing mechanical stresses, compounding the metabolic abnormalities (6). Finally, ischemia and reperfusion can trigger apoptosis, as a consequence of damage to mitochondria and leakage of cytochrome c, or through activation of receptormediated apoptotic signaling cascades (7).