Full regeneration of deer antlers, a bona fide epimorphic process in mammals, is in defiance of the general rule of nature. Revealing the mechanism underlying this unique exception would place us in a better position to promote organ regeneration in humans. Antler regeneration takes place in yearly cycles from its pedicle, a permanent protuberance on the frontal bone. Both growing antlers and pedicles consist of internal (cartilage and bone) and external components (skin, blood vessels, and nerves). Recent studies have demonstrated that the regeneration of both internal and external components relies on the presence of pedicle periosteum (PP). PP cells express key embryonic stem cell markers (Oct4, Nanog, and SOX2) and are multipotent, so are termed antler stem cells. Now it is clear that proliferation and differentiation of PP cells directly forms internal antler components; however, how PP initiates and maintains the regeneration of external antler components is thus far not known. Based on the direct as well as indirect evidence that is presented in this review, I put forward the following hypothesis to address this issue. The full regenerative ability of external antler tissue components is achieved through PP‐derived chemical induction and PP‐derived mechanical stimulation: the former triggers the regeneration of these external components, whereas the latter drives their rapid elongation. Eventual identification of the putative PP‐derived chemical factors would open up a new avenue for devising effective therapies for lesions involving each of these tissue components, be they traumatic, degenerative, or linked to developmental (genetic) anomalies. (Part C) 96:51–62, 2012. © 2012 Wiley Periodicals, Inc.