We demonstrated previously that grafts of fetal dopaminergic neurons can reverse motor deficits induced by the toxin, MPTP, in parkinsonian, non-human primates as a test of feasibility of cellular repair in a complex nervous system. Clinical trials followed in both young and aged Parkinson patients with encouraging results including patients who showed substantial improvement in mobility as well as reduction in medications for up to 8-10 years. Nevertheless, many patients experienced modest or little benefit and some evidence exists that grafted neurons, after ten years, may show signs of neuropathology. Some recipients also experienced marked dyskinesias which suggests a lack of afferent control of grafted neurons perhaps resulting in excess dopamine. These results suggest that methods must be found to restore neurological control of grafted neurons. We have explored the use of multiple, stepping stone grafts to guide axonal growth from grafts of dopamine neurons, placed into appropriate sites in the brain stem, to anatomically correct target sites in the basal forebrain. Immunochemical analysis of the retrograde transported marker, fluoro-gold, demonstrated extended growth from substantia nigra grafts to the striatum, i.e. a distance of 8-10mm. Dopamine fiber outgrowth was extensive and appeared to pass through several bridge grafts en route to the distant target. The results encourage the view that tract reconstruction may be possible in adult human brain. We also have explored the use of human neural stem cells to ameliorate parkinsonian symptoms in non-human primates with encouraging results. Cells implanted into the striatum showed a remarkable migratory ability and were found in the substantia nigra where a small number appeared to differentiate into dopamine neurons. The majority became growth factor producing glia that could provide beneficial effects on host dopamine neurons. In addition, we double-labeled for BrdU, a marker for cell division, and neurofilament-M to identify mature neurons of stem cell origin. BrdU positive neurons were found in other major brain regions and were seen as pyramidal neurons of the cerebral cortex and hippocampus, multipolar neurons of the thalamus, and elsewhere. While the factors that stimulated wisespread migration and differentiation need clarification, these findings point to the use of neural stem cells to treat a variety of neurodegenerative disorders including Alzheimer's disease. ALS, spinal cord injury and others.