Objective: What lies behind the remarkable potential of some organisms to rebuild themselves after injury, and why aren’t mammals better at it? The limited restorative capacity of human tissues has been attributed to the loss of adequate cell replacement coupled with persistent inflammation with increasing age. Our imaginations have been captivated by mounting evidence for populations of stem cells in adult tissues, perhaps set aside earlier in the embryo, that might be coerced into regenerative service in later life. Stem cells have attracted huge scientific and public interest, not only because they bear the promise of miracle cures for age-related diseases, but also because their medical use is so appealing: stem-cell therapy would augment the human body’s own regenerative capacity, which declines as we grow older. Materials and Methods: Our approach has been to develop mouse models to tinker with mechanisms at work in the mammalian response to damage, disease and ageing, by reducing the impediments to effective regeneration. The laboratory mouse is widely considered the model organism of choice for studying the diseases of humans, from whom they differ in only a tiny fraction of their genetic material. A distinguished history of classical genetic experimentation in the mouse has recently gathered speed with the advent of powerful new tools to manipulate the murine genome. The recent launch of several internationally sponsored initiatives for systematic mouse mutagenesis on a large scale using various genetics strategies, along with high throughput phenotyping pipelines, underscores the utility of the mouse for interpreting the mammalian genome, and for generating increasingly more accurate models of human disease. Results: Interventions in growth factor delivery using mouse models support the feasibility of recapturing regenerative capacity by modulating key signaling pathways to restore injured or degenerating mammalian tissues. In each model, distinct cellular components are employed, providing new targets for clinical intervention. Conclusion: The appropriate source of cells for therapeutic applications in regenerative medicine is hotly debated, and much work must be done before stem cell therapy can become a medical reality; even the recent explosion of information on stem cell pluripotency has still not brought us a clear understanding of the underlying molecular biology in any system. Other mechanisms at work in the normal regeneration process may be more successfully harnessed to increase the efficiency of stem cell-mediated regeneration.