Abstract: Worldwide morbidity and mortality of acute myocardial infarction (AMI) and related heart failure are still high.While effective early reperfusion of the criminal coronary artery after a confirmed AMI is the typical and effective treatment at present, collateral myocardial ischemia reperfusion injury (MIRI) and pertinent cardio-protection are still challenging to address and have inadequately understood mechanisms.One important reason might be that AMI is multifactorial, causing cardiomyocyte death via multiple mechanisms, as well as affecting other cell types, including platelets, fibroblasts, endothelial and smooth muscle cells, and immune cells.Many cardioprotective strategies act through common end-effectors and may be suboptimal in patients with comorbidities.Therefore, unveiling the related multitarget strategies participating in triggering and resisting the pathobiology of MIRI is a promising and valuable frontier.The review specifically focuses on the recent MIRI advances that are supported by multitarget strategies and new targets under development in order to bring the rational combination of multitarget therapies up to date, as well as to identify findings that may facilitate the new drug of novel targets.