Organ regeneration occurs in anamniotes (fish and amphibians) while is absent in amniotes (reptiles, birds and mammals). An evolutionary hypothesis is presented to explain the loss of organ regeneration in amniotes. The aquatic life in fish or the initial aquatic and later terrestrial life in amphibians requires complex life cycles after embryonic development. One or more larval stages that occupy different ecological niches are necessary in fish to reach the final adult stage, generally through metamorphosis. This is a post-embryonic process determined by genes that are constitutive of the genome of fish and amphibians, and that can also be re-utilized during adult life to regenerate injured or lost organs. During the adaptation to terrestrial niches, the larval stages disappeared and a direct development evolved with the formation of the amniote egg in reptiles and birds or the blastocysts in mammals. The genome for developing larvae and metamorphosis was therefore eliminated from the life cycle of amniotes. The loss of genes utilized for metamorphosis determined also the loss of the capability to regenerate organs in adults, especially of the neural organization of the nervous system. The cellular immune system that in anamniotes was operating in metamorphic destruction of larval tissues, in amniotes became no longer tolerant to embryonic-larval antigens. The loss of genes operating during metamorphosis and presence of intolerant immune cells determined the inability to regenerate organs in amniotes. Efforts of regenerative medicine must overcome these genetic and immune barriers to induce organ regeneration.