Ischemia-reperfusion injury underlies many pathological conditions, including ischemic heart disease, which is a major cause of death worldwide [1]. Myocardial ischemia-reperfusion injury results from an interruption in the blood supply to a region of the heart and is most often the result of acute coronary occlusion. Significant injury also occurs upon reperfusion of the ischemic region, as additional myocardial damage results from the formation of reactive oxygen species [2], which can trigger cell death by activating pro-apoptotic and/or necrotic signaling pathways in cardiomyocytes [3]. The issue of cell death is of paramount importance in the heart since cardiomyocytes are terminally differentiated, and aside from cardiac progenitor cells, the myocardium is very limited with regard to endogenous regenerative capabilities [4]. Cardioprotective interventions hold great promise for lessening the detrimental effects of myocardial ischemia-reperfusion injury [5] and have been shown to reduce contractile dysfunction, arrhythmogenesis and cell death in animal models [6],[7],[8],[9]. In 1986, Murry and Reimer originally described the powerful cardioprotective phenomena known as ischemic preconditioning (IPC), whereby brief exposure to periods of ischemia and reperfusion serves to protect the heart against a more prolonged ischemic insult [6]. However, IPC must be performed prior to the onset of ischemia, thereby limiting clinical applicability. Since the initial discovery of IPC, additional protective mechanisms with greater clinical applicability have been described, including ischemic postconditioning [10], and pharmacologic agents such as adenosine [11], cyclosporine [12], and nitric oxide [13]. Mechanistically, there is much that remains to be defined, but these interventions are thought to converge on similar cytoprotective signaling pathways that may include the reperfusion injury salvage kinase (RISK) pathway, which is comprised primarily of phosphoinositide 3-kinase/Akt, ERK1/2, and glycogen synthase kinase 3 beta [14]. Although research devoted to the elucidation of cardioprotective signaling pathways has been ongoing for nearly 40 years, few experimental discoveries have translated successfully into effective therapeutics, and currently, the only established intervention that consistently reduces infarct size in humans is early coronary artery reperfusion, which still has the potential to cause additional myocardial injury as mentioned above. The recent study from Liu et al.[15] brings a fresh perspective on potential therapeutic approaches for the treatment of ischemic heart disease with the use of recombinant protein, namely, the membrane repair protein mitsugumin-53.