In recent years, basic research has enabled a better understanding of the molecular and cellular basis of myocardial ischemia. In this context, cardiac mitochondria have been shown to perform an important role, being essential to energy production and ionic homeostasis, and thus controlling cardioprotection and cell death. Knowledge of these facts has led to the development of new therapeutic strategies for myocardial ischemia, aiming to modify its biochemical pathways and to preserve mitochondrial function. It has also led to a better understanding of the cellular and subcellular effects of classical anti-ischemic drugs, revealing that most of them also have a direct impact on cardiac mitochondrial function. This article summarizes what is currently known regarding the pharmacological modulation of mitochondrial function during ischemia and reperfusion and how it can induce cardioprotection in coronary artery disease patients.