Wnt proteins are a large family of diffusible factors that play important roles in embryonic development, including axis patterning, cell fate specification, proliferation, and axon development. It was recently demonstrated that Ryk (receptor related to tyrosine kinase) is a conserved high-affinity Wnt receptor, and that Ryk-Wnt interactions guide corticospinal axons down the spinal cord during development. Here, we report that the Ryk-Wnt signal mediates the inhibition of corticospinal axon growth in the adult spinal cord. The expression of Wnt-5a is induced in reactive astrocytes around the injury site following a spinal cord injury. In vitro, Wnt-5a inhibits the neurite growth of postnatal cerebellar neurons by activating RhoA/Rho-kinase. In rats with thoracic spinal cord contusion, intrathecal administration of a neutralizing antibody to Ryk resulted in significant axonal growth of the corticospinal tract and enhanced functional recovery. Thus, reexpression of the embryonic repulsive cues in adult tissues contributes to the failure of axon regeneration in the central nervous system.