Spinal cord injury results in a remarkable level of spontaneous plasticity that occurs at the level of injury and beyond in discrete circuitry of the brain. The restorative and maladaptive reorganization of injured and spared circuitry results in a new operational state that is not yet fully understood but likely has vast implications for the efficacious implementation of neuromodulation therapy. Neuromodulation offers the potential to disrupt or reset the activation state of both intact and injured spinal cord circuitry that, in many cases, unmasks the functionality of residual volitional pathways or facilitates the assembly of new adaptive and restorative connections. We believe that invasive or noninvasive transcutaneous stimulation of the spinal cord, peripheral nerves and muscles-motor units, in combination with the use of task-oriented rehabilitation can be productively applied to potentiate spontaneous plasticity to restore a wide variety of motor functions. In the future, therapeutic protocols for neuromodulation will be elevated as designs take into consideration the physiological preparedness of the patient, the type and level of injury, the importance of targeting the adaptive activity arriving from segments above and below the level of injury, as well as to reverse maladaptive changes in spinal networks that are likely lesion specific. Experimental results in animals and humans support the exciting premise that the chronically injured nervous system retains significant, inherent activity dependent adaptability that remains to be fully harnessed for restoration of motor function through therapeutic stimulation.