Following disease or injury to the CNS, the formation of a glial scar represents a physical and molecular barrier to repair. Although some therapies have promoted axonal sprouting into the lesion site, these fibres are often tangled and disorientated. To date, there has been little evidence of regenerating fibres successfully exiting the glial scar to reform functional connections. Furthermore, remyelination after disease or injury is limited, often consisting of shorter internodes of myelin and thinner sheaths. Thus, potential therapies aimed at enhancing CNS repair should support the outgrowth of neurites, guide their exit from the glial scar and perhaps aid remyelination. Since multiple factors impede the regeneration of the CNS, a combinatorial approach to therapies including cell-transplantation may be a more promising strategy.