We are on the brink of harnessing the cell's natural defenses against ischemia and reperfusion injury after years of research into the destructive and protective mechanisms involved. Since the discovery of ischemic preconditioning, the surface receptors and signal transduction pathways underlying this phenomenon have been clarified, but many questions remain about the downstream targets that ultimately protect the cell. ATP-sensitive K(+) (K(ATP)) channels are thought to play a role in protection, but their mechanism of action has been unclear. Accumulating evidence now suggests that the location of the K(ATP) channels relevant to cytoprotection may be on the mitochondrial inner membrane instead of on the sarcolemma of the cardiac cell. This review discusses recent findings and unanswered questions about the role of K(ATP) channels in preconditioning and protection.