Regeneration describes the remarkable innate potential of our cells—especially those of mesenchymal origin—to restore both structure and function of the complex tissue after injury. This process is far more sophisticated than simple wound closure; as it almost certainly involves a dynamic interplay between the cellular biomechanics, energy homeostasis and transcriptional timing. In optimal scenarios—such as in embryonic tissues or select adult tissues—these mechanisms enable scar-free healing and even the regeneration of complex structures. However, in adult mammals, this regenerative capacity is often restricted by the factors linked to age-related decline at the systemic level. Advancing our understanding of the bio-thermodynamics driving self-healing potential, through application of big data, holds significant promise for future therapies.