The article discusses the role of glial inhibition in the adult central nervous system (CNS) and its impact on axon regeneration. The CNS environment, including inhibitory molecules in myelin and proteoglycans associated with astroglial scarring, presents a significant barrier to successful axon regeneration. The molecular basis of these inhibitory influences and their contributions to long-distance axon repair and structural plasticity are evaluated. Recent studies have identified several inhibitory molecules, such as Nogo, myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), Sema4D/CD100, and ephrin B3, which can restrict axon growth. These inhibitors are either constitutively expressed or induced after injury and form multiple layers of inhibition. The glial scar, composed of reactive astrocytes and chondroitin sulfate proteoglycans (CSPGs), further enhances the inhibitory environment. Receptor mechanisms for myelin inhibition involve the Nogo-66 receptor (NgR) and its co-receptors, such as p75, TROY, and LINGO1. Intracellular signaling pathways, particularly RhoA and ROCK, mediate the effects of these inhibitors. In vivo studies have shown limited success in promoting axon regeneration by targeting these inhibitory pathways, possibly due to compensatory mechanisms and the reduced intrinsic regenerative capacity of mature axons. The article also discusses the physiological roles of glial inhibition in the intact CNS, suggesting that these mechanisms may serve to stabilize neural circuitry during development. Finally, it explores the potential for therapeutic strategies to overcome glial inhibition and promote functional recovery after CNS injury.The article discusses the role of glial inhibition in the adult central nervous system (CNS) and its impact on axon regeneration. The CNS environment, including inhibitory molecules in myelin and proteoglycans associated with astroglial scarring, presents a significant barrier to successful axon regeneration. The molecular basis of these inhibitory influences and their contributions to long-distance axon repair and structural plasticity are evaluated. Recent studies have identified several inhibitory molecules, such as Nogo, myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), Sema4D/CD100, and ephrin B3, which can restrict axon growth. These inhibitors are either constitutively expressed or induced after injury and form multiple layers of inhibition. The glial scar, composed of reactive astrocytes and chondroitin sulfate proteoglycans (CSPGs), further enhances the inhibitory environment. Receptor mechanisms for myelin inhibition involve the Nogo-66 receptor (NgR) and its co-receptors, such as p75, TROY, and LINGO1. Intracellular signaling pathways, particularly RhoA and ROCK, mediate the effects of these inhibitors. In vivo studies have shown limited success in promoting axon regeneration by targeting these inhibitory pathways, possibly due to compensatory mechanisms and the reduced intrinsic regenerative capacity of mature axons. The article also discusses the physiological roles of glial inhibition in the intact CNS, suggesting that these mechanisms may serve to stabilize neural circuitry during development. Finally, it explores the potential for therapeutic strategies to overcome glial inhibition and promote functional recovery after CNS injury.