Epidermis and epithelia lining the ocular surface, the oral cavity, the pharynx, the oesophagus, the larynx, and the vagina, called stratified squamous epithelia (SSE), contain stem/progenitor cells that support renewal and repair. Under appropriate conditions, these cells can be massively expanded in culture. Restoration of the integrity and the function of SSE is obtained by transplantation and engraftment of the autologous cultivated stem cells in case of several severe clinical conditions (e.g., extensive third-degree burns, limbal deficiency). Successful gene therapy for hereditary SSE disorders has also been achieved by means of correction of the genetic defect in cultivated autologous keratinocyte stem cells. However, the mechanisms controlling engraftment of the transplanted stem cells remain poorly understood, leading to unpredictable clinical results. Further fundamental investigations to explore the behaviour of the transplanted stem cells and their plasticity, anticipating the regulatory affairs main concerns, are needed for successful cell and gene therapy