The ischemic heart requires reperfusion using clinical interventions, such as coronary artery bypass graft surgery, in order to recover. Despite recent developments in myocardial protection techniques, reperfusion damage still occurs, and significant morbidity remains a problem. Therefore, the search continues for techniques that will limit myocardial damage and that will enhance recovery upon reperfusion. Mitochondria are known to be intimately involved in the processes that lead to cell death following reperfusion, in both necrotic and apoptotic forms of cell death, and so are potential targets for protective intervention. In this review, we consider several aspects of mitochondrial function that we believe to be possible targets for myocardial protection; namely, mitochondrial Ca²⁺ transport, the permeability transition pore, and improved mitochondrial substrate supply. We discuss work by ourselves and others in these areas, and also consider the recently proposed role of mitochondrial ATP-dependent K⁺ channels in mediating myocardial protection by ischemic preconditioning. Finally, we describe use of cardioplegic solutions in the clinical setting, and discuss how improved understanding of the aspects of mitochondrial function summarised above may lead to better protective strategies in the future.