The regenerative capacity of central nervous system (CNS) axons after injury is severely impaired compared to axons of the peripheral nervous system (PNS). We hypothesized that mechanisms both intrinsic and extrinsic to the neuron influence the ability of CNS axons to regenerate. To investigate this hypothesis we explored two model systems. In the first model system, we identified a regeneration transcriptome in injured corticospinal motor neurons that is associated with enhanced central axon regeneration after spinal cord injury. The genetic mechanisms identified in this model include cAMP-Erk-CREB, Huntingtin, NFE2L2, ephrin and semaphorin signaling, and provide a dataset for potential therapeutic intervention to improve axonal regeneration in vivo after spinal cord injury. In the second model, we tested the hypothesis that glial cells of the peripheral nerve, Schwann cells, are an essential mechanism contributing to central axonal regeneration after "conditioning" lesions, wherein injury to the peripheral branch of a dorsal root ganglion sensory neuron enhances regeneration of the central branch of the sensory neuron. The gene encoding Low-density lipoprotein Receptor-related Protein-1 (LRP1) was conditionally deleted in Schwann cells, impairing the survival and function of Schwann cells after injury; animals with Schwann cell-specific deletion of LRP1 exhibited a significant reduction in axon regeneration in vitro and a trend towards central sensory axon regeneration after conditioning lesions, confirming that glial cells exhibit an essential but partial role in supporting axonal regeneration. Overall, these studies identify novel molecular and cellular mechanisms that influence central axon regeneration, and suggest therapeutic approaches to improve neural repair after CNS injury.