This selected article represents a comprehensive and brilliant reflection on the past, present and future of cardiac regenerative and reparative therapies with stem cells. Beginning with a clear explanation of the basic pathobiology of the myocardium and its natural healing mechanisms after injury, the author convincingly demonstrates that the heart behaves as a terminally differentiated organ, with very limited intrinsic reparative tools. Then the article summarizes the main basic experiments and animal studies that have explored all putative mechanisms of action of stem cells during the last 30 years, reviewing the phases of myocardial remodeling and the pros and cons of every cell type. Regarding products, the author leaves as the only relevant option for cardiac repair that of tissue engineering combined with cells derived from embryonic or induced pluripotent stem cells. Then the main published clinical trials are analysed from a critical point of view to finally enumerate the most important caveats and barriers of clinical research with stem cells. Regulatory considerations are explained to objectively face the fact of fraudulent research and article retractions that have arisen during the last years in the field. Finally, the manuscript offers a sensible and prudent advice to better think next research efforts and further investments in the field of cardiac repair, at least until biological mechanisms of action become clearly demonstrated.