The labyrinth of intricate circuitry makes the central nervous system quite inept to regenerate its functionality after a devastating injury. Apart from targeting the major inhibitory effect of glial scar associated proteoglycans like chondroitin sulfate and the reactive glial cell secreted inflammatory and growth inhibitory molecules, the other major regeneration stalling component that arises after severe CNS injury is myelin and its associated proteinaceous debris comprising myelin-associated glycoprotein (MAG), neurite outgrowth inhibitor protein (NOGO), and oligodendrocyte myelin glycoprotein (OMgp). Various experiments revealed that, upon neutralization of those myelin inhibitors, regeneration could occur satisfactorily. Any therapeutic intervention which can obliterate the myelin-associated axonal growth-inhibitory protein components will be successful in revival and normal restoration of a patient's life. The sole purpose of this Viewpoint is to address the inhibitory role of these myelin-associated proteins, usually located at the lesion site, and few recent research trends to explore the scope of therapeutically overcoming the regeneration barrier in healing massive CNS injury. © 2020 American Chemical Society.