The therapeutic efficacy of mesenchymal stem cell (MSC) transplantation has recently been attributed to exosomes when a single bolus of MSC exosomes prior to reperfusion of ischemic myocardium ameliorates reperfusion injury and reduces infarct size. In this article we review the therapeutic efficacy of MSC exosome in ameliorating cell intrinsic factors in reperfusion injury by focusing on the proteome complementation of exosomes and reperfused myocardium. The well-documented ATP deficit and initiation of apoptosis during ischemia and reperfusion were recently found to be underpinned by a proteomic deficit in enzymes critical for fatty acid oxidation, glycolysis and tricarboxylic acid cycle, and a proteomic surplus of proapoptotic proteins. Interestingly, this deficit in glycolytic enzymes was complemented by an abundance in MSC exosomes and the surplus of proapoptotic proteins was circumvented by CD73 that could increase survival signaling through the activation of reperfusion injury salvage kinases. Together, this provides a window of opportunity for the cells to repair and regenerate thus constituting the rationale for the therapeutic efficacy of MSC exosomes.