In this review the author outlines the early history of clinical and scientific research upon the inability of the CNS in man to successfully regenerate following injury. As we proceed into the 21st Century we have gained a far greater understanding of the molecular biology, pathology and other factors that lead to the adult CNS being non-supportive and indeed actively inhibitory to axonal regrowth. On the basis of these recent advances in knowledge, the author outlines possible therapeutic approaches that may enable more effective CNS regeneration to be accomplished in the future.