Partial reprogramming achieved by the transient expression of the transcription factors (TFs) Oct4, Sox2, Klf4 and C-Myc (abbreviated OSKM) can erase aging and damage features in cells, leading to increased healthspan, lifespan and tissue regeneration. Recent reports suggest that the mechanisms of partial reprogramming may share some similarities with natural dedifferentiation and regeneration. Both processes appear to involve the transient repression of somatic identity through the sequestration of somatic identity TFs to noncanonical sites, which are opened by the high expression of pioneer TFs, leading to transient dedifferentiation into a fetal-like state. Here, we review the reported benefits of partial reprogramming on tissue regeneration and propose a common mechanism of epigenetic remodeling with natural regeneration after tissue injury.