Abstract: The mature central nervous system (CNS, composed of the brain, spinal cord, olfactory and optic nerves) is unable to regenerate spontaneously after an insult, both in the cases of neurodegenerative diseases (for example Alzheimer’s or Parkinson’s disease) or traumatic injuries (such as spinal cord lesions). In the last 20 years, the field has made significant progress in unlocking axon regrowth. The lesion’s environment has been well characterized, notably the contribution of the glial scar and myelin debris-associated molecules to axon regeneration inhibition. Surprisingly, the modulation of these factors only promotes limited axon regrowth (Varadarajan et al., 2022). Thus, the focus has progressively shifted from the environment of the injured axons to the neurons themselves. Several regenerative models have been developed targeting different steps of gene expression from epigenetics to translation processes. For example, regarding transcription regulation, it has been found that the modulation of transcription factors, such as suppressor of cytokine signaling 3, a negative regulator of Janus kinases/signal transducers and activators of transcription pathway, the Krüppel-like factors family or c-myc could promote axon regeneration (Varadarajan et al., 2022). Activating the mammalian target of rapamycin pathway, a major regulator of protein translation also promotes regeneration (Varadarajan et al., 2022). Moreover, combinatorial approaches such as activation of mammalian target of rapamycin, Janus kinases/ signal transducers and activators of transcription pathways along with c-myc overexpression lead axon regeneration up to several millimeters from the eye to the brain (Belin et al., 2015). Even if these results are very exciting, functional recovery remains a pending issue. Indeed, recent work highlights that regrowing axons is not the only aspect necessary for circuit formation and several unexpected roadblocks have been uncovered: (i) the majority of regenerating axons do not reach their proper targets, (ii) nor do they regularly form synapses when they do reach their targets, and (iii) myelination in a regenerative context is still poorly characterized. In this article, we will discuss these challenges.