Ischemic diseases in an aging population pose a heavy social encumbrance. Moreover, current therapeutic approaches, which aimed to prevent or minimize ischemia-induced damage, are associated with relevant costs for healthcare systems. Early reperfusion by primary percutaneous coronary intervention (PPCI) has undoubtedly improved patient’s outcomes; however, the prevention of long-term complications is still an unmet need. To face these hurdles and improve patient’s outcomes, novel pharmacological and interventional approaches, alone or in combination, reducing myocardium oxygen consumption or supplying blood flow via collateral vessels have been proposed. A number of clinical trials are ongoing to validate their efficacy on patient’s outcomes. Alternative options, including stem cell-based therapies, have been evaluated to improve cardiac regeneration and prevent scar formation. However, due to the lack of long-term engraftment, more recently, great attention has been devoted to their paracrine mediators, including exosomes (Exo) and microvesicles (MV). Indeed, Exo and MV are both currently considered to be one of the most promising therapeutic strategies in regenerative medicine. As a matter of fact, MV and Exo that are released from stem cells of different origin have been evaluated for their healing properties in ischemia reperfusion (I/R) settings. Therefore, this review will first summarize mechanisms of cardiac damage and protection after I/R damage to track the paths through which more appropriate interventional and/or molecular-based targeted therapies should be addressed. Moreover, it will provide insights on novel non-invasive/invasive interventional strategies and on Exo-based therapies as a challenge for improving patient’s long-term complications. Finally, approaches for improving Exo healing properties, and topics still unsolved to move towards Exo clinical application will be discussed.