Spinal cord injury (SCI) results in degeneration of oligodendrocytes leading to axonal demyelination, white matter degeneration and consequently functional deficits. We and others have shown the potential of transplanting neural precursor cells (NPCs) or activating endogenous precursor cells for oligodendrocyte differentiation following SCI. Further studies, however, indicate the capacity of NPCs for replacement of myelinating oligodendrocytes is challenged by inhibitory alterations in the local microenvironment of post-SCI. Under profound modifications in the extracellular milieu of the injured spinal cord, resident or transplanted NSCs give rise predominantly to astrocytes at the expense of oligodendrocytes. Also challenging, the majority of NPC-derived oligodendorcyte precursor cells either undergo cell death or fail to fully mature into myelinating phenotype. Moreover, the myelin sheath that is formed by the newly formed oligodendrocytes lacks the normal thickness. As a result of these limitations, we find that many of the surviving axons either show evidence of abnormal myelination or undergo retrograde degeneration during the chronic phase of SCI. We have recently found that robust and chronic depletion of axonally localized Neuregulin-1 (Nrg-1) after SCI correlates closely with the poor replacement of oligodendrocytes. Nrg-1 is an essential factor for axons and oligodendrocytes development and function. Interestingly, restoration of the deficient level of Nrg-1 after SCI by intrathecal infusion of recombinant Nrg-1 was able to promote oligodendrocyte differentiation of spinal cord derived NPCs. Additionally, our parallel studies demonstrate that reactive astrocyte driven increases in matrix chondroitin sulfate proteoglycans (CSPGs) inhibit the potential of NPCs for oligodendrocytes differentiation and survival in vitro and in SCI. we find that targeting CSPGs by their pharmacological removal from the injured spinal cord using chondroitinase ABC (ChABC) or inhibiting CSPGs receptors in NPCs allows better integration of NPCs and increase their ability for oligodendrocyte differentiation. This talk will discuss our recent research findings in these areas. Careful elucidation of molecules/processes contributing to impaired oligodendrocyte differentiation in the post-SCI milieu is essential for developing effective remyelination therapies for white matter repair following SCI or other demyelinating disorders.