Cardiac diseases are the leading cause of death and reach epidemic proportions with aging. Advanced heart disease results from an abrupt or progressive loss of contractile cardiomyocytes. Following percutaneous coronary intervention and revascularization regenerative medicine aims at effectively repair damaged tissue and replacement of lost cardiomyocytes. However, mixed results were obtained from trials using bone marrow-derived stem cells. Benefits were rather attributed to paracrine effects leading to inhibition or reverse of negative remodeling processes than to regeneration of viable cardiomyocytes. Thus the aim of regenerative medicine, in particular stem cell research, to generate viable cardiac muscle has so far not been achieved in humans, reflecting our incomplete understanding of underlying biological mechanisms. Moreover, there is growing evidence that substantial person-to-person differences in the outcome of stem cell therapy exists. We here review our present knowledge in evolving stem cell based cardiovascular medicine and highlight personalized aspects of stem cell interventions.