The experience accumulated in cardiac cell therapy suggests that regeneration of extensively necrotic myocardial areas is unlikely to be achieved by the sole paracrine effects of the grafted cells but rather requires the conversion of these cells into cardiomyocytes featuring the capacity to substitute for those which have been irreversibly lost. In this setting, the use of human pluripotent embryonic stem cells has a strong rationale. The experimental results obtained in animal models of myocardial infarction are encouraging. However, the switch to clinical applications still requires to address some critical issues, among which optimizing cardiac specification of the embryonic stem cells, purifying the resulting progenitor cells so as to graft a purified population devoid from any contamination by residual pluripotent cells which carry the risk of tumorigenesis and controlling the expected allogeneic rejection by clinically acceptable methods. If the solution to these problems is a pre-requisite, the therapeutic success of this approach will also depend on the capacity to efficiently transfer the cells to the target tissue, to keep them alive once engrafted and to allow them to spatially organize in such a way that they can contribute to the contractile function of the heart. © 2012 Société de Biologie.