For neurorehabilitation of patients with spinal cord injury (SCI), the traditional emphasis on social adaptation is being expanded to include strategies that promote plasticity and regeneration in the central nervous system. Such strategies are needed to optimize recovery of neurological function. For example, the known dependence of most cellular processes on physical activity has led to the novel concept that activity is important in neural repair. This hypothesis has given rise to activity-based restoration therapies (ABRT), which aim to optimize neural activity in the damaged spinal cord, particularly below the injury level. Here, we review the basic science and clinical evidence supporting the lifelong use of ABRT for recovery from spinal cord injury. We define and describe ABRT, and discuss its components, its clinical applications, its relationship to medical management of spinal cord injury, and the potential influences of medications on recovery. We also discuss the health benefits of ABRT under physiological and pathological conditions. We stress that lifelong ABRT is required to optimize return of function and to allow patients to benefit from any " cures" that will be discovered.