Physical rehabilitation following spinal cord injury-related paralysis has traditionally focused on teaching compensatory techniques, thus enabling the individual to achieve day-to-day function despite significant neurological deficits. But the concept of an irreparable central nervous system (CNS) is slowly being replaced with evidence related to CNS plasticity, repair, and regeneration, all related to persistently maintaining appropriate levels of neurological activity both below and above the area where the damage occurred. It is now possible to envision functional repair of the nervous system by implementing rehabilitative interventions. Making the transition from "bench to bedside" requires careful analysis of existing basic science evidence, strategic focus of clinical research, and pragmatic implementation of new therapeutic tools. Activity, defined as both function specific motor task and exercise appears to be a necessity for optimization of functional, metabolic, and neurological status in chronic paralysis. Crafting a comprehensive rehabilitative intervention focused on functional improvement through neurological gains seems logical. The terms activity-based restorative therapies, activity-based therapies, and activity-based rehabilitation have been coined in the last 10 years to describe a new fundamental approach to deficits induced by neurological paralysis. The goal of this approach is to achieve activation of the neurological levels located both above and "below" the injury level using rehabilitation therapies. This article reviews basic and clinical science evidence pertaining to implementation of physical activity and exercise as a therapeutic tool in the management of chronic spinal cord-related neurological paralysis.