The failure of axon regeneration in the injured adult CNS has been ascribed to axon growth inhibitory molecules expressed by the resident glial cell populations, especially oligodendrocytes. Unlike their adult counterparts, however, early embryonic neurons are able to send lengthy axons through myelinated fiber tracts when transplanted into the adult brain. One explanation is that they have yet to express receptors for factors that inhibit the growth of older neurons. To test this possibility, we have used the cryoculture technique to study the regeneration of rat central and peripheral neurons, over a developmental period that encompasses the stages before, during, and after target contact, when cultured on either unmyelinated (neonatal) or myelinated (adult) optic nerve tissue sections. Early embryonic (days 14-15) retinal ganglion cells extended neurites on neonatal optic nerve, but few grew on adult optic nerve. In the case of early embryonic dorsal root ganglion neurons, however, neurite outgrowth on either neonatal optic nerve or on adult optic nerve was extensive. This response declined sharply with age. In contrast, neurite outgrowth by dorsal root ganglion neurons on laminin substrata remained relatively constant (> 80% extended neurites) over the same period. This suggests that (a) inhibition of neurite outgrowth within the optic nerve is mediated not only by oligodendrocytes, but also by molecules expressed prior to the onset of myelination; (b) neurons acquire receptors for these inhibitors only late in embryonic development; (c) differences exist between developing central and peripheral neurons in the response to myelin-associated axon-growth inhibitors.