Small lesions of the adult central nervous system (CNS) often have a good prognosis with extensive functional recovery based in part on spontaneous neuritic sprouting and rearrangements of projections. This is well documented for the cortex, but these changes can also occur in the spinal cord. Nogo-A is a protein present in CNS myelin that inhibits neurite growth. Models of spinal cord injury (SCI) in rats and macaque monkeys demonstrate that treatment with function-blocking antibodies of Nogo-A results in an upregulation of growth-specific proteins, enhanced regenerative and compensatory sprouting of fibers, and the formation of new functional connections in the spinal cord. In animals with unilateral sensorimotor cortex lesions followed by Nogo-A antibody treatment, fibers from the intact corticofugal system crossed the midline, supplying innervation to the denervated brain stem or spinal cord. Behavioral tests showed marked improvements of functional recovery in the Nogo-A antibody treated spinal cord- or brain-injured animals. A Phase I clinical trial applying anti-Nogo-A antibody to subjects with acute SCI has been successfully conducted and a multicentric, multinational Phase II trial is currently in preparation.