This chapter focuses on the translation of extracellular cues to intracellular programs that are determinants of regenerative capacity. While the extracellular environment in the adult central nervous system (CNS) contains molecules that act as growth inhibitors, both in vitro and in vivo, co-culture experiments suggest that much of the failure of axon regeneration seen in the adult CNS can be attributed to a developmental reduction in the intrinsic regenerative ability of neurons. An irreversible loss of regenerative ability occurs at birth in rat retinal ganglion cell (RGC). Another indication of the importance of neuronintrinsic factors in determining the regenerative ability of axons is the heterogeneity in regenerative ability expressed by axons of different neurons growing through the same environment. The intrinsic growth capacity of an injured neuron is influenced by its external environment. Finally, the chapter presents some of the important extrinsic signals, and considers the intrinsic drivers of regeneration.