Identification of multi-potent stem cells and potential for cardiomyocyte proliferation in the adult mammalian heart has promoted a revision of the dogma that the heart is a post-mitotic organ with limited regenerative reserve. Stem cell and/or regeneration therapies may therefore have significant clinical impact in patients with ischaemic injury and heart failure, the most significant causes of death in our society. My laboratory has developed a quantitative framework for characterising a population of MSC-like stem cells from adult mouse hearts that likely represent precursor cells for stromal and vascular lineages in health, and fibrosis-inducing cells in genetic and chronic diseases. Such cells (cardiac colony-forming units-fibroblast; cCFU-F) show long-term growth in vitro and self-maintenance in vivo, and show multipotency for a variety of mesodermal and trans-germ layer lineages in surrogate assays. Growth and potency are profoundly compromised by aging, ischaemic disease and inhibition of pathways that maintain the stem cell niche. I will present our recent data on the characterisation of cCFU-F, their lineage origins in development and compromised behaviour in disease and aging, and molecules regulating their cell cycle status and stem character.