The term stromal cells is referred to cells of direct or indirect (hematopoietic) mesenchymal origin, and encompasses different cell populations residing in the connective tissue, which share the ability to produce the macromolecular components of the extracellular matrix and to organize them in the correct spatial assembly. In physiological conditions, stromal cells are provided with the unique ability to shape a proper three-dimensional scaffold and stimulate the growth and differentiation of parenchymal precursors to give rise to tissues and organs. Thus, stromal cells have an essential function in the regulation of organ morphogenesis and regeneration. In pathological conditions, under the influence of local pro-inflammatory mediators, stromal cells can be prompted to differentiate into myofibroblasts, which rather express a fibrogenic phenotype required for prompt deposition of reparatory scar tissue. Indeed, scarring may be interpreted as an emergency healing response to injury typical of evolved animals, like mammals, conceivably directed to preserve survival at the expense of function. However, under appropriate conditions, the original ability of stromal cells to orchestrate organ regeneration, which is typical of some lower vertebrates and mammalian embryos, can be resumed. These concepts underline the importance of expanding the knowledge on the biological properties of stromal cells and their role as key regulators of the three-dimensional architecture of the organs in view of the refinement of the therapeutic protocols of regenerative medicine.