Cardiovascular medicine has recently implemented multiple pre-clinical and clinical trials intended to identify a feasible and safe approach for cell-based heart repair. In the myocardium, several recent studies demonstrate the benefit of ATSCs to include direct contribution to neovasculogenesis and de novo cardiogenesis, in addition to indirect paracrine action for cardioprotection, neoangiogenesis, and neuron spindle formation. Furthermore, treatment with ATSCs has demonstrated a diminished propensity for arrhythmogenic risk without any evidence for uncontrolled growth, systemic complications, or tumorigenic change. Engrafted adipose stem cells improves the myocardial function with the capacity for contribution both via direct differentiation and indirect regenerative paracrine signaling in the host myocardial microenvironment. Adipose tissue resource holds great promise in providing the raw stem cell material to generate therapeutic products in the treatment of cardiovascular disease. However, due to the heterogenous nature of derived stem cells, further evaluation is needed to delineate the mechanism of stem cell benefit within the myocardium and implement next generation approaches such as linage specification and combinatorial stem cell therapy.