Abstract: Neural stem and progenitor cell (NSPC) transplantation has emerged as a promising therapeutic strategy for replacing lost neuronal populations and repairing damaged neural circuits following nervous system injury and disease. A great deal of experimental work has investigated the biology of NSPC grafting in preclinical animal models; more recently, NSPC transplantation has advanced to clinical trials. However, there are fundamental questions regarding the biology of NSPC grafting that warrant further investigation. Here, we focus on the importance of the regional identity of donor cells for determining outcomes following transplantation. We discuss key findings in models of traumatic brain injury and Parkinson’s disease, focusing on how concepts learned from this work may have potential applications for transplantation following spinal cord injury (SCI).