The failure of axons in the central nervous system (CNS) to regenerate has been considered the main factor limiting recovery from spinal cord injury (SCI). Impressive gains in identification of growth-inhibitory molecules in the CNS led to expectations that their neutralization would lead to functional regeneration. However, results of therapeutic approaches based on this assumption have been mixed. Recent data suggest that neurons differ in their ability to regenerate through similar extracellular environments, and moreover, they undergo a developmental loss of intrinsic regenerative ability. Factors mediating these intrinsic regenerative abilities include expression of (1) receptors for inhibitory molecules such as the myelin-associated growth inhibitors and developmental guidance molecules, (2) surface molecules that permit axon adhesion to cells in the path of growth, (3) cytoskeletal proteins that mediate the mechanics of axon growth, and (4) molecules in the intracellular signaling cascades that mediate responses to chemoattractive and chemorepulsive cues. In contrast to axon development, regeneration might involve internal protrusive forces generated by microtubules, either through their own elongation or by transporting other cytoskeletal elements such as neurofilaments into the axon tip. Because of the complexity of the regenerative program, one approach will probably be insufficient to achieve functional restoration of neuronal circuits. Combination treatments will be increasingly prominent. SCI is a debilitating and costly condition that compromises pursuit of activities usually associated with an independent and productive lifestyle. This article discusses recent advances in neurorehabilitation that can improve the life quality of individuals with SCI.