Simple SummaryThe present MS proposes a new hypothesis that motivates why only some animals can regenerate their organs. This derives from their simple body constitution, environment where they live, evolutionary story and life cycles. Only water-dwelling animals or animals that include drastic body changes in their life (metamorphosis) can regenerate when they are adults after an injury or organ-loss. This derives from the re-utilization of numerous genes that were previously utilized for metamorphosis. Humans and the remaining terrestrial animals have lost or altered the functionality of these genes during their evolution, and therefore cannot regenerate anymore. Whether regenerative gene therapies can help to improve human regeneration is a big challenge for the future of regenerative medicine.AbstractThe ability to heal or even regenerate large injuries in different animals derives from the evolution of their specific life cycles during geological times. The present, new hypothesis tries to explain the distribution of organ regeneration among animals. Only invertebrates and vertebrates that include larval and intense metamorphic transformations can broadly regenerate as adults. Basically, regeneration competent animals are aquatic while terrestrial species have largely or completely lost most of the regeneration ability. Although genomes of terrestrial species still contain numerous genes that in aquatic species allow a broad regeneration (“regenerative genes”), the evolution of terrestrial species has variably modified the genetic networks linking these genes to the others that evolved during land adaptation, resulting in the inhibition of regeneration. Loss of regeneration took place by the elimination of intermediate larval phases and metamorphic transformations in the life cycles of land invertebrates and vertebrates. Once the evolution along a specific lineage generated species that could no longer regenerate, this outcome could not change anymore. It is therefore likely that what we learn from regenerative species will explain their mechanisms of regeneration but cannot or only partly be applied to non-regenerative species. Attempts to introduce “regenerative genes” in non-regenerative species most likely would disorder the entire genetic networks of the latter, determining death, teratomas and cancer. This awareness indicates the difficulty to introduce regenerative genes and their activation pathways in species that evolved genetic networks suppressing organ regeneration. Organ regeneration in non-regenerating animals such as humans should move to bio-engineering interventions in addition to “localized regenerative gene therapies” in order to replace lost tissues or organs.