Reconstitution of complex multi-tissue organs is one of the most impressive feats of biology and is observed across regeneration-competent vertebrate species, including teleost fish (e.g., zebrafish), urodeles (e.g., axolotls and newts), and some lizards. Regenerative ability within these species ranges from muscle (including cardiac), skeletal structures, to complex systems such as the brain, spinal cord and parts of the eye which are all capable of structural and functional repair following injury (Tanaka and Ferretti, 2009). In stark contrast, re-establishment of multi-tissue structures is very rarely observed following embryogenesis in regeneration-incompetent mammals. Regrowth of digit tips is the most dramatic example of mammalian regeneration, but pales in comparison to other species in the animal kingdom. Undoubtedly, a complete recapitulation of complex organs or structures in mammals will remain out of reach for a considerable time; however, an improved understanding of regenerative mechanisms would likely enhance the development of novel regenerative medicine strategies. Here we focus on the diversity and commonalities of stem cells, which could underlie complex tissue regeneration.