The intrinsic growth capacity of neurons in the CNS declines during neuronal maturation, while neurons in the adult PNS are capable of regeneration. Injured mature PNS neurons require activation of an array of regeneration-associated genes to regain axonal growth competence. Accumulating evidence indicates a pivotal role of epigenetic mechanisms in transcriptional reprogramming and regulation of neuronal growth ability upon injury. In this review, we summarize the latest findings implicating epigenetic mechanisms, including histone and DNA modifications, in axon regeneration and discuss differential epigenomic configurations between neurons in the adult mammalian CNS and PNS.