After more than 20 years following the introduction of regenerative medicine to address the problem of cardiac diseases, still questions arise as to the best cell types and materials to use to obtain effective clinical translation. Now that it is definitively clear that the heart does not have a consistent reservoir of stem cells that could give rise to new myocytes, and that there are cells that could contribute, at most, with their pro-angiogenic or immunomodulatory potential, there is fierce debate on what will emerge as the winning strategy. In this regard, new developments in somatic cells’ reprogramming, material science and cell biophysics may be of help, not only for protecting the heart from the deleterious consequences of aging, ischemia and metabolic disorders, but also to boost an endogenous regeneration potential that seems to be lost in the adulthood of the human heart.