Severe lesions of the rodent or human spinal cord lead to permanent paralysis of the legs. Here, we review novel evidences suggesting that interventions combining pharmacological and electrical stimulations of the spinal cord have a high potential to promote the recovery of locomotion following severe spinal cord injuries in humans. These strategies are based on the existence of webs of circuits and receptors embedded in the spinal motor infrastructure that each modulate specific aspects of locomotor movements. We show that chemical or electrical stimulations can engage specific elements of this spinal machinery, thus resulting in distinct patterns of locomotion in paralyzed spinal rats. In turn, simultaneous chemical stimulations of neural receptors and/or electrical stimulations of multiple spinal segments can synergistically facilitate locomotor movements. These preliminary results provide a strong rationale for the development of neuroprosthetic chemotrode and electrode arrays that would enable a detailed and distributed access to the different elements of the spinal motor infrastructure. Such novel biomedical technologies may offer unparalleled potential to induce multiple and flexible locomotor states in paralyzed subjects.