In the past 20 years, there have been several approaches to achieve cardioprotection or cardiac regeneration using a vast variety of cell therapies and remote ischemic pre-conditioning (RIPC). To date, substantial proof that either cell therapy or RIPC has the potential for clinically relevant cardiac repair or regeneration of cardiac tissue is still pending. Preclinical trials indicate that the secretome of cells in situ (during RIPC) as well as of transplanted cells may exhibit cardioprotective properties in the acute setting of cardiac injury. The secretome generally consists of cell-specific cytokines and extracellular vesicles (EVs) containing microRNAs (miRNAs). It is currently hypothesized that a subset of known miRNAs play a crucial part in the facilitation of cardioprotective effects. miRNAs are small non-coding RNA molecules that inhibit post-transcriptional translation of messenger RNAs (mRNAs) and play an important role in gene translation regulation. It is also known that one miRNAs usually targets multiple mRNAs. This makes predictability of pharmacokinetics and mechanism of action very difficult and could in part explain the inferior performance of various progenitor cells in clinical studies. Identification of miRNAs involved in cardioprotection and remodeling, the composition of miRNA profiles, and the exact mechanism of action are important to the design of future cell-based but also cell-free cardioprotective therapeutics. This review will give a description of miRNA with cardioprotective properties and a current overview on known mechanism of action and potential missing links. Additionally, we will give an outlook on the potential for clinical translation of miRNAs in the setting of myocardial infarction and heart failure.