During development, guidance molecules play a key role in the formation of complex circuits required for neural functions. With the cessation of development, this exuberant growth process slows and stabilizes, and inhibitory molecules expressed by glia prevent initial attempts for axonal regeneration. In this review, we discuss the expression patterns and relative contribution of several guidance molecules on the regenerative process. Injury to the immature CNS or species capable of regenerating exhibit a complete or partial recapitulation of their developmental guidance patterns, whereas similar injuries to adult mammals results in altered expression that acts to further hinder regeneration. Manipulations of guidance molecules after injury have been used to control detrimental effects of axon sprouting and target regenerating axons within the spinal cord.