Mammalian organ regeneration is the ultimate goal of regenerative biology and medicine. The most dramatic example of organ replacement is known as ‘epimorphic regeneration’ and occurs mainly in amphibians, in which phenotypically committed cells are reprogrammed at the amputation plane toward a stem cell phenotype. The result is the complete regrowth of an amputated structure from an anatomically complex stump. Although mammals cannot regenerate amputated limbs, the regeneration of the hair follicle end bulb following amputation results in regeneration of the dermal papilla (DP) and the entire organ structure of the hair follicle, and can serve as a model to interrogate this process. To analyze the molecular events underlying this phenomenon, we adapted a mouse model, from previous work carried out in rat and human HFs. The mystacial pads of adult mice were incised to expose vibrissa follicles and end bulbs were excised. DP and end bulb regeneration was examined at several time points up to 21 days by histology and immunohistochemistry. We followed the formation of the new dermal sheath using molecular markers, which appears to be reprogrammed from the remaining dermal sheath after amputation. We observed pronounced cellular invasion of the mesenchyme around the amputated end bulb. This preceded the restoration of the DP which coincided with positive Prom-1 expression. Following expansion of epithelial cells down the hair shaft to below the level of the cut, regression and consolidation of a P-cadherin labeled basal epithelium above the newly formed basement membrane preceded differentiation of a new matrix. Similar to the molecular mechanisms involved in epimorphic regeneration in lower vertebrates, dedifferentiation of dermal sheath cells to progenitor/stem cells and their reprogramming to repopulate the DP may occur via the epigenetic reactivation of developmental regulatory genes that function during embryogenesis.