Spinal cord and brain injuries trigger complex cellular and molecular interactions within the central nervous system (CNS) to repair tissue damage. The response of glial cells, particularly astrocytes, and the influence of inflammation on wound healing processes significantly impact the overall morbidity and permanent disability. The failure of neuronal regeneration after spinal cord injury is influenced by inflammatory cell activation, reactive astrogliosis, and the production of both growth-promoting and inhibitory extracellular molecules. Despite the historical view that glial scars were merely mechanical barriers to regeneration, inhibitory molecules in the forming scar and methods to overcome them suggest molecular modification strategies to promote neuronal growth and functional regeneration. Unlike myelin-associated inhibitory molecules, which remain at static levels before and after CNS trauma, inhibitory extracellular matrix molecules are dramatically upregulated during the inflammatory stages after injury, providing a window of opportunity for therapeutic interventions. While high-dose methylprednisolone steroid therapy has not proven effective, other strategies to modulate inflammation and change the composition of inhibitory molecules in the extracellular matrix show promising evidence that rehabilitation after spinal cord and brain injury can significantly improve outcomes.Spinal cord and brain injuries trigger complex cellular and molecular interactions within the central nervous system (CNS) to repair tissue damage. The response of glial cells, particularly astrocytes, and the influence of inflammation on wound healing processes significantly impact the overall morbidity and permanent disability. The failure of neuronal regeneration after spinal cord injury is influenced by inflammatory cell activation, reactive astrogliosis, and the production of both growth-promoting and inhibitory extracellular molecules. Despite the historical view that glial scars were merely mechanical barriers to regeneration, inhibitory molecules in the forming scar and methods to overcome them suggest molecular modification strategies to promote neuronal growth and functional regeneration. Unlike myelin-associated inhibitory molecules, which remain at static levels before and after CNS trauma, inhibitory extracellular matrix molecules are dramatically upregulated during the inflammatory stages after injury, providing a window of opportunity for therapeutic interventions. While high-dose methylprednisolone steroid therapy has not proven effective, other strategies to modulate inflammation and change the composition of inhibitory molecules in the extracellular matrix show promising evidence that rehabilitation after spinal cord and brain injury can significantly improve outcomes.