The molecular composition of the mitochondrial permeability transition pore (MPTP) will be considered briefly and evidence presented for a central role for the phosphate carrier in addition to a facilitating role for cyclophilin D (CyP-D) and a regulatory role for the adenine nucleotide translocase (ANT). The importance of both calcium and especially oxidative stress in opening the MPTP will be stressed. It will be shown how these factors cause MPTP opening during reperfusion following a prolonged period of ischaemia leading to the irreversible necrotic damage known as reperfusion injury. Preventing this MPTP opening is cardioprotective and the mechanism by which known cardioprotective strategies achieve this will be discussed with a particular emphasis on ischaemic preconditioning. This involves exposure of hearts to two or three brief cycles of ischaemia and reperfusion before the prolonged ischaemia. We will show how this reduces the oxidative stress experienced by mitochondria at the end of ischaemia and during early reperfusion. This, in turn, decreases the sensitivity of MPTP opening to calcium and so leads to less MPTP opening and necrotic tissue damage. We find no evidence that any protein kinases translocate to the mitochondria to induce these effects, nor for changes in the phosphorylation of mitochondrial proteins exerted by endogenous protein kinases. Rather decreased oxidation of critical thiol residues on the ANT can provide an adequate explanation for the protection. Other preconditioning protocols such as temperature preconditioning and urocortin also act in this way.