Spinal cord injury is a devastating condition of the central nervous system (CNS), often resulting in severe loss of tissue, functional impairment, and only limited repair. Studies over the last few years have shown that response to the insult and spontaneous attempts at repair are multiphasic processes, with varying and sometimes conflicting requirements. This knowledge has led to novel strategies of therapeutic intervention. Our view is that a pivotal role in repair, maintenance, healing, and cell renewal in the CNS, as in other tissues, is played by the immune system. The mode and timing of intervention must be carefully selected, however, as the capacity of the CNS to tolerate local repair mechanisms is limited. Studies have shown that the spontaneously evoked early innate response to CNS injury is characterized by invasion of neutrophils and is unfavorable for cell survival. This is followed by a response of the resident innate immune cells (microglia), which however cannot supply all the needs of the damaged tissue; moreover, once evoked, and for as long as the damage persists, the microglial response remains beyond the capacity of the CNS to tolerate it. Immune-based clinical intervention is most effective in improving functional and morphological recovery when delayed for a certain period. Effective intervention might be in the form of (1) local injection of "alternatively activated" macrophages, (2) systemic injection of dendritic cells specific to CNS antigens, or (3) T-cell-based vaccination. The treatment of choice depends on the severity of the insult, the site of injury, the therapeutic window, and safety considerations.