Axon regeneration in the mammalian adult central nervous system (CNS) is limited by an intrinsically low capacity for axon growth in many CNS neurons. In contrast, embryonic, peripheral, and many nonmammalian neurons are capable of successful regeneration. Numerous studies have compared mammalian CNS neurons to their counterparts in regenerating systems in an effort to identify candidate genes that control regenerative ability. This review summarizes work using this comparative strategy and examines our current understanding of gene function in axon growth, highlighting the emergence of genome-wide expression profiling and high-throughput screening strategies to identify novel regulators of axon growth.