The skin is constantly exposed to environmental insults and requires effective repair processes to maintain its protective function. Wound healing is severely compromised in people with congenital absence of structural proteins of the skin, such as in dystrophic epidermolysis bullosa, a severe congenital mechanobullous disorder caused by mutations in collagen type VII. Remarkably, stem cell transplantation can ameliorate deficiency of this skin-specific structural protein in both animal models and in children with the disorder. Healthy donor cells from the hematopoietic graft migrate to the injured skin; simultaneously, there is an increase in the production of collagen type VII, increased skin integrity, and reduced tendency to blister formation. How hematogenous stem cells from bone marrow and cord blood can alter skin architecture and wound healing in a robust, clinically meaningful way is unclear. We review the data and the resulting hypotheses that have a potential to illuminate the mechanisms for these effects. Further modifications in the use of stem cell transplantation as a durable source of extracellular matrix proteins may make this regenerative medicine approach effective in other cutaneous and extracutaneous conditions.