Ischemic heart disease remains the leading cause of death worldwide. Mitochondria are the power plant of the cardiomyocyte, generating more than 95% of the cardiac ATP. Complex cellular responses to myocardial ischemia converge on mitochondrial malfunction which persists and increases after reperfusion, determining the extent of cellular viability and post-ischemic functional recovery. In a quest to ameliorate various points in pathways from mitochondrial damage to myocardial necrosis, exhaustive pharmacologic and genetic tools have targeted various mediators of ischemia and reperfusion injury and procedural techniques without applicable success. The new concept of replacing damaged mitochondria with healthy mitochondria at the onset of reperfusion by auto-transplantation is emerging not only as potential therapy of myocardial rescue, but as gateway to a deeper understanding of mitochondrial metabolism and function. In this chapter, we explore the mechanisms of mitochondrial dysfunction during ischemia and reperfusion, current developments in the methodology of mitochondrial transplantation, mechanisms of cardioprotection and their clinical implications.