Heart failure (HF), caused by ischemic-induced cardiomyopathy, has still a poor prognosis. Although cell therapy has drawn extraordinary controversy since applied, it is still followed as a potential approach to treat ischemic HF. In recent work by Bolli and colleagues, transendocardial injection with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs) was given alone or in combination in a multicentre trial approach. The 7 centres enrolled 125 patients with a left ventricular ejection fraction of 29% and a scar size of 19% (NYHA class II/III), in which the treatment was shown to be safe and feasible. Even with maximal guideline-based therapy, both MSC as CPC were associated with improved clinical outcomes (MACE and quality of life, 6- and 12-months post injection), but without clear ventricular functional or structural changes (MRI scans). These observations, once more, suggest a strong systemic or paracrine mechanism of effect in these patients. Interestingly, no additive effects of MSC and CPC could be observed on a structural myocardial level as was previously indicated in preclinical work, although this Phase II design is also not designed to claim such observations. These findings are generating more support to further explore how paracrine signals can support HF patients. At the same time, they also promote that for a structural change of the myocardium, other approaches are warranted, such as maybe suggested by work this month on remuscularization via engineered heart patches.