Traumatic brain injury (TBI) results from a physical insult to the head and is the leading killer and cause of disability in children and young adults, yet there are currently no effective clinical treatments. Neural stem cell (NSC) transplantation presents a promising option for treatment following TBI because of the possibility of replacing a variety of cell types compromised by injury and responding to cues after injury. Direct transplantation of suspended cells into the brain has been plagued by a lack of integration and survival of the cells, presumably due to a loss of the normal architecture crucial to cell function. A key component of this native environment is the extracellular matrix (ECM), which plays a crucial role in directing normal brain development. We investigated the effect of ECM molecules on neural stem cell (NSC) behavior in vitro and found that simple presentation of ECM proteins had profound effects on adhesion, migration, and differentiation of NSC. These processes were further shown to be primarily mediated through specific members of the Pi integrin family of cell adhesion molecules. We also provide evidence that transplantation paradigms which present ECM molecules on a three-dimensional scaffold enhances survival and integration of transplants into the injured brain, which correlates with our basic in vitro results. In addition we have characterized the long term effects of neural stem cell therapy into the injured brain and demonstrate functional recovery as early as one week post transplant which was sustained for a period of 1 year. Together these data suggest that neural stem cell therapy may provide beneficial effects after CNS injury and that ECM based tissue engineering strategies may enhance the functional efficacy of such therapies.