Failure of axon regeneration after central nervous system (CNS) injuries results in permanent functional deficits. Numerous studies in the past suggested that blocking extracellular inhibitory influences alone is insufficient to allow the majority of injured axons to regenerate, pointing to the importance of revisiting the hypothesis that diminished intrinsic regenerative ability critically underlies regeneration failure. Recent studies in different species and using different injury models have started to reveal important cellular and molecular mechanisms within neurons that govern axon regeneration. This review summarizes these observations and discusses possible strategies for stimulating axon regeneration and perhaps functional recovery after CNS injury.