Autophagy is an intracellular lysosomal-mediated catabolic process in which senescent or damaged proteins and organelles are sequestered by double membrane-limited vesicles called autophagosomes, and then degraded by lysosomes. While the role of autophagy in different pathological states is context-dependent, it has been shown that during cardiac ischemia, autophagy is upregulated as a cardioprotective adaptation. We recently demonstrated that Rheb, a small GTP-binding protein that directly activates the complex 1 of the mechanistic target of rapamycin, is a critical regulator of autophagy during cardiac ischemia. We found that cardiac Rheb/mTORC1 signaling is activated in a deregulated manner during ischemia in obesity and metabolic syndrome. This uncontrolled activation of the Rheb/mTORC1 pathway leads to autophagy inhibition and to a reduction of myocardial tolerance to ischemia. This data further supports the relevance of autophagy as a fundamental protective mechanism during myocardial ischemia and suggests that reactivation of autophagy, in particular through the inhibition of Rheb/mTORC1 signaling may represent a promising therapeutic option to treat subjects with an acute myocardial infarction, particularly those affected by metabolic derangements. This review will deal with the biological significance of autophagy in cardioprotection.