Large spinal cord or brain injuries lead to life-long, often major functional deficits. In contrast, smaller lesions of the CNS often have a good prognosis with extensive functional recovery; the underlying mechanisms are not well understood, however. In adult rats, spinal cord injury transecting the hindlimb corticospinal (CST) axons or stroke-mediated destruction of parts of the motor cortex induce spontaneous sprouting of spared fibers in the upper spinal cord and brain stem. Rehabilitative training enhances both the functional recovery of precision movements and the anatomically demonstrated fiber growth. Following hindlimb CST axotomy, forelimb sensory connections expand to the former hindlimb motor cortex that now is re-connected to the forelimb spinal cord, demonstrating a major map shift of the sensory and motor somatotopic representations. In all these cases, however, extent and length of fiber growth was limited to about 0.2 – 2 mm. Twenty years ago, our group has discovered the presence of specific neurite growth inhibitiory factors in myelin of the CNS, among which the membrane protein Nogo-A, currently the most potent known neurite growth inhibitor. Function blocking antibodies against Nogo-A have been generated and applied to rats and macaque monkeys with spinal cord injuries as well as animals with strokes in the sensory-motor cortex. Biochemical readouts showed an up-regulation of growth specific proteins. On the anatomical level, injured fibers showed enhanced regenerative sprouting as well as long-distance regeneration with formation of large terminal arbors. Simultaneously, spared fiber tracts showed enhanced compensatory sprouting, often covering relatively long distances. In animals with cortical strokes, fibers from the intact corticobulbar or corticospinal system crossed the midline, supplying innervation to the denervated brain stem or spinal cord under the influence of anti- Nogo-A antibodies. Behavioural experiments for locomotion, grid and beam walk, swimming, as well as skilled forelimb reaching showed marked improvements of functional recovery in the Nogo-A antibody treated injured animals. These results show that the spontaneously occurring repair processes after CNS injury can be potentiated by the functional suppression of the endogenous neurite growth inhibitory protein Nogo-A. In collaboration with Novartis, a clinical trial is corrently conducted in acutely spinal cord injured patients.