Spinal cord injury (SCI) is a disastrous event causing irreversible loss of both sensory and motor function. After SCI, both ascending dorsal column axons and descending corticospinal tract (CST) axons undergo rapid degeneration that is subsequently followed by slow axonal dieback and retraction bulb formation. Pre-clinical studies over the last two decades using genetic and, to a lesser extent, pharmacological approaches have identified several molecules that regulate intrinsic axon regeneration after SCI. However, accumulating evidence suggests that the efficacy of intrinsic pro-regenerative molecules to enhance axon regeneration is considerably different between ascending dorsal column and descending CST axons following SCI. Here I describe the different molecules targeting intrinsic regeneration and their efficacy in triggering dorsal column and CST axon regeneration after SCI. First, I will briefly describe the general anatomy of dorsal column and CST axons as well as their acute and chronic response after SCI. Then, I will review the latest genetic and pharmacological studies identifying molecules targeting intrinsic axon regeneration and the efficacy of such molecules in promoting dorsal column and CST axon regeneration after SCI. Next, I will review accumulating evidence suggesting important differences in regenerative response between dorsal column and CST axons upon targeting intrinsic pro-regenerative molecules. Finally, I will suggest future research directions to uncover the downstream molecular mechanisms responsible for differences in regenerative response between dorsal column and CST axons following SCI.