Stem cell therapy (SCT) raises the hope for cardiac regeneration in ischemic hearts. However, underlying molecular mechanisms for repair of dead myocardium by SCT in the ischemic heart is poorly understood. Growing evidences suggest that cardiac matrix stiffness and differential expressions of miRNAs play a crucial role in stem cell survival and differentiation. However, their roles on transplanted stem cells, for myocardial repair of the ischemic heart, remain unclear. Transplanted stem cells may act in an autocrine and/or paracrine manner to regenerate the dead myocardium. Paracrine mediators such as stem cell-derived exosomes are emerging as a novel therapeutic strategy to overcome some of the limitations of SCT. These exosomes carry microRNAs (miRNAs) that may regulate stem cell differentiation into a specific lineage. MicroRNAs may also contribute to stiffness of surrounding matrix by regulating extracellular matrix (ECM) turnover. The survival of transplanted stem cell depends on its autophagic process that maintains cellular homeostasis. Therefore, exosomes, miRNAs, extracellular matrix turnover, and autophagy may have an integral role in improving the efficacy of SCT. This review elaborates the specific roles of these regulatory components on cardiac regeneration in the ischemic heart during SCT.