Ischemic heart disease can lead to myocardial infarction (MI), a major cause of morbidity and mortality worldwide. Adoptive transfer of multiple stem cell types into failing human hearts has demonstrated safety however the beneficial effects in patients with cardiovascular disorders have been modest. Modest improvement in patients with cardiac complications warrants identification of a novel stem cell population that possesses effective reparative properties and improves cardiac function after injury. Recently we have shown in a mouse model and a porcine pre-clinical animal model, that cortical bone derived stem cells (CBSCs) enhance cardiac function after MI and/or ischemia-reperfusion injury. These beneficial effects of allogeneic cell delivery appear to be mediated by paracrine mechanisms rather than by transdifferentiation of injected cells into vessels and/or immature myocytes. This review will discuss role of CBSCs in cardiac wound healing. After having modest beneficial improvement in most of the clinical trials, a critical need is to understand the interaction of the transplanted stem cells with the ischemic cardiac environment. Transplanted stem cells are exposed to pro-inflammatory factors and activated immune cells and fibroblasts, but their interactions remain unknown. We have shown that CBSCs modulate different processes including modulation of the immune response, angiogenesis, and restriction of infarct sizes after cardiac injury. This review will provide information on unique protective signature of CBSCs in rodent/swine animal models for heart repair that should provide basis for developing novel therapies for treating heart failure patients.