There have been tremendous advances in identifying cellular and molecular mechanisms constraining axon growth and strategies have been developed to overcome regenerative failure. However, reproducible and meaningful functional recovery remains elusive. An emerging reason is that neurons possess subtype-specific activation requirements. Much of this evidence comes from studying retinal ganglion cells following optic nerve injury. This review summarizes key neuropathologic events following spinal cord injury, and draws on findings from the optic nerve to suggest how a similar framework may be used to dissect and manipulate the heterogeneous and subtype-specific responses of neurons useful to target for spinal cord injury.