The inability of the human heart to effectively repair itself after acute ischaemic injury has driven the search for efficacious means of promoting cardiac regenerative growth. Central to this has been the emergence of cell-based strategies to stimulate and augment both myocardial regeneration and neovascularization. Autologous cell transplantation of a variety of adult progenitor cells has been taken forward in clinical trials and, in parallel, investigators have begun to focus on the activation of resident cardiac cell populations as a means to stimulate endogenous repair. The latter approach depends on characterizing native progenitors with self-renewal, clonality, multipotency and arguably an analogous embryological counterpart. Recently, we have focused on adult EPDCs (epicardium-derived progenitor cells), which, when induced by the actin monomer-binding protein Tbeta4 (thymosin beta4), are able to revert to their embryonic phenotype and give rise to endothelial cells and vascular smooth muscle cells ex vivo. Studies are ongoing to determine whether activated adult EPDCs can contribute to bona fide neovascularization in the injured adult mammalian heart proper, as a therapeutic means to support surviving cardiac muscle cells and sustain regenerating myocardium.