Stem cell based strategies are fast track, novel, alternative therapies to repair damaged tissues of chronic diseases and have raised great hopes for incurable heart failure in particular. Various stem/progenitor populations are being put forward as potential therapies to achieve cardiac repair/regeneration. The recently described cardiac-derived progenitor/stem cells (CPC) received intensive investigation given their inherent programming to reconstitute the damaged myocardium. Clinical application of autologous cells provided convincing evidence of feasibility and efficiency but limited availability, and pointed out that the use of allogenic cells via cell banks, if proven safe, are a more realistic proposition for cardiac repair. Our recent findings reinforced this notion by demonstrating that the inherent immune features of human CPC shift their behavior within the allogenic settings towards the delivery of signals that promote the development, maintenance, and functioning of a PD-L1/PD1 mediated immune-modulator antiinflammatory reparative response, rather than a detrimental conventional allogenic process. In this context, we discuss how this allogenic immune response, if balanced, can be part of the dynamic and durable mechanisms proposed as critical to sustain cardiac regeneration and repair and propose, based on knowledge of transplantation practice strategies, to reach such balance.