Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Purpose of review Outcomes of stem cell trials in patients with advanced heart failure have been divergent, which has raised some scepticism about this therapy and led to recommending slowing clinical trials until basic issues have been more thoroughly addressed. It is therefore timely and relevant to examine the current data and discuss how recent findings may change the perspectives of stem cell therapy. Recent findings The most important recent change has been a shift in the mechanistic paradigm. Although the initial objective of stem cells was to physically replace dead cardiomyocytes and build a new electromechanically integrated myocardial tissue, it is now recognized that the unavoidable death of most of the transplanted cells makes this objective unrealistic. Indeed, the primary mechanism of action of the cells seems to be paracrine through the release of factors activating the endogenous signalling pathways, leading to cardioprotection. This hypothesis has several implications. First, it leads to focus on the efficiency of early retention, rather than on sustained survival, which, in turn, implies improving delivery approaches, largely through an increased reliance on adjunctive biomaterials; second, it may rationalize the use of allogeneic cells as long as their rejection is delayed to give them enough time for releasing the signalling biomolecules; and, finally, it raises the possibility that transplantation of cells could be replaced by the delivery of their sole secretome, possibly under the form of microvesicles. Summary Put together, these approaches could streamline the translational process and enhance large-scale clinical applications.