PTEN deletion enhances the regenerative ability of adult corticospinal neurons. This study demonstrates that PTEN/mTOR signaling plays a critical role in controlling the regenerative capacity of corticospinal (CST) neurons in mice. After development, CST axons lose their regrowth potential, accompanied by reduced mTOR activity. Axonal injury further decreases mTOR activity in these neurons. Conditional deletion of PTEN, a negative regulator of mTOR, increases mTOR activity, promoting compensatory sprouting of uninjured CST axons and enabling regeneration of injured CST axons past a spinal cord lesion. Regenerating CST axons can also reform synapses in spinal segments distal to the injury. Modulating neuronal intrinsic PTEN/mTOR activity could be a potential therapeutic strategy for promoting axon regeneration and functional recovery after spinal cord injury. Spinal cord injury often results in permanent paralysis due to the failure of injured axons to regenerate in the adult central nervous system (CNS). Functional recovery after CNS injury can be achieved through sprouting of spared non-injured axons or regeneration of lesioned axons. Despite numerous efforts to stimulate both collateral and regenerative growth of CST axons, success has been limited, suggesting that injured CST axons are especially refractory to regeneration. While various approaches have been tested, including removal of extracellular inhibitory molecules, delivery of neurotrophic factors, and grafting permissive substrates, regeneration of injured CST axons remains challenging. The study shows that the age- and injury-dependent down-regulation of mTOR activity is a major cause of the lack of regeneration of optic nerve axons after injury. Genetic activation of mTOR promotes successful optic axon regeneration. However, it is unknown whether this is specific to retinal ganglion neurons or applicable to other CNS neurons. Here, it is shown that enhancement of the mTOR pathway strikingly enhances regrowth of adult CST axons following different types of injury models. The results indicate that PTEN deletion prevents mTOR down-regulation and increases CST sprouting. PTEN deletion is sufficient for maintaining high mTOR activity characteristic of young neurons in adult cortical neurons, and for these neurons to launch a robust sprouting response after injury. CST regeneration after T8 dorsal hemisection and complete crush injury after neonatal PTEN deletion was observed. Regenerating CST axons were able to form synapses in spinal segments distal to the injury. These findings suggest that modulating neuronal intrinsic PTEN/mTOR activity could be a potential therapeutic strategy for promoting axon regeneration and functional recovery after spinal cord injury.PTEN deletion enhances the regenerative ability of adult corticospinal neurons. This study demonstrates that PTEN/mTOR signaling plays a critical role in controlling the regenerative capacity of corticospinal (CST) neurons in mice. After development, CST axons lose their regrowth potential, accompanied by reduced mTOR activity. Axonal injury further decreases mTOR activity in these neurons. Conditional deletion of PTEN, a negative regulator of mTOR, increases mTOR activity, promoting compensatory sprouting of uninjured CST axons and enabling regeneration of injured CST axons past a spinal cord lesion. Regenerating CST axons can also reform synapses in spinal segments distal to the injury. Modulating neuronal intrinsic PTEN/mTOR activity could be a potential therapeutic strategy for promoting axon regeneration and functional recovery after spinal cord injury. Spinal cord injury often results in permanent paralysis due to the failure of injured axons to regenerate in the adult central nervous system (CNS). Functional recovery after CNS injury can be achieved through sprouting of spared non-injured axons or regeneration of lesioned axons. Despite numerous efforts to stimulate both collateral and regenerative growth of CST axons, success has been limited, suggesting that injured CST axons are especially refractory to regeneration. While various approaches have been tested, including removal of extracellular inhibitory molecules, delivery of neurotrophic factors, and grafting permissive substrates, regeneration of injured CST axons remains challenging. The study shows that the age- and injury-dependent down-regulation of mTOR activity is a major cause of the lack of regeneration of optic nerve axons after injury. Genetic activation of mTOR promotes successful optic axon regeneration. However, it is unknown whether this is specific to retinal ganglion neurons or applicable to other CNS neurons. Here, it is shown that enhancement of the mTOR pathway strikingly enhances regrowth of adult CST axons following different types of injury models. The results indicate that PTEN deletion prevents mTOR down-regulation and increases CST sprouting. PTEN deletion is sufficient for maintaining high mTOR activity characteristic of young neurons in adult cortical neurons, and for these neurons to launch a robust sprouting response after injury. CST regeneration after T8 dorsal hemisection and complete crush injury after neonatal PTEN deletion was observed. Regenerating CST axons were able to form synapses in spinal segments distal to the injury. These findings suggest that modulating neuronal intrinsic PTEN/mTOR activity could be a potential therapeutic strategy for promoting axon regeneration and functional recovery after spinal cord injury.