--- - |2- During myocardial ischemia–reperfusion (I/R), HSP70 is overexpressed and exerts numerous cardioprotective effects against I/R injury. In this review, we highlight these protective effects of HSP70, elucidate the mechanisms involved, and provide several HSP70‐driven therapeutic potentials against myocardial I/R injury. In summary, it is considered that HSP70 is a promising therapeutic target against myocardial I/R injury. Acute myocardial infarction is a major cause of death worldwide. The most important therapy for limiting ischemic injury and infarct size is timely and efficient myocardial reperfusion treatment, which may instead induce cardiomyocyte necrosis due to myocardial ischemia–reperfusion (I/R) injury. Heat shock protein 70 (HSP70), a stress‐inducible protein, is overexpressed during myocardial I/R. The induced HSP70 is shown to regulate several intracellular proteins (e.g., transcription factors, enzymes, and apoptosis‐related proteins) and signaling pathways (e.g., c‐Jun N‐terminal kinase pathway and extracellular‐signal‐regulated kinase 1/2 pathway), forming a complicated network that contributes to reducing reactive oxygen species accumulation, improving calcium homeostasis, inhibiting cellular apoptosis, thereby enhancing the stress adaption of myocardium to I/R injury. In addition, the extracellular HSP70, which is released from injured cardiomyocytes during I/R, acts as a proinflammatory mediator that results in cell death, while the intracellular HSP70 exerts antiinflammatory effects by suppressing proinflammatory signaling pathways. Notably, HSP70 is induced and contributes to the cardioprotection in several types of preconditioning and postconditioning. Meanwhile, it is shown that the cardioprotective effectiveness of preconditioning‐induced HSP70 (e.g., hyperthermia preconditioning‐induced HSP70) can be impaired by certain pathological conditions, such as hyperlipidemia and hyperglycemia. Thus, we highlight the widespread cardioprotective involvement of HSP70 in preconditioning and postconditioning and elucidate how HSP70‐mediated cardioprotection is impaired in these pathological conditions. Furthermore, several therapeutic potentials of HSP70 against myocardial I/R injury and potential directions for future studies are also provided in this review. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1190-1207, February 2019. '