There has been considerable progress in our understanding of cardiac cell metabolism in health and disease, yet important gaps remain in basic knowledge and its translation to clinical care. AMP-activated protein kinase (AMPK) functions either to conserve ATP or to promote alternative methods of ATP generation. Since the discovery of AMPK more than three decades ago and demonstration of its expression in the heart, interest has grown exponentially in this major fuel gauge as a modulator of the cellular response to ischemia. Such pathway may potentially explain the strong association between metabolic syndrome and ischemic heart disease. Still missing from our most recent cardiology textbooks, this article aims to summarize our understanding so far of the role of AMPK in coordinating the cellular response to ischemic stress and reperfusion injury in the heart. We aim to provide a focused update on the pharmacological agents activating AMPK for treatment of diabetes that show potential cardioprotective effects. Our hope is to stimulate future researchers to the potential benefits of harnessing the AMPK signaling pathway, or better one of its novel downstream targets for the treatment of myocardial ischemia.