Perinatal hypoxic-ischemic brain injury and stroke in the developing brain remain important causes of chronic neurologic morbidity. Emerging data suggest that transplantation of umbilical cord blood-derived stem cells may have therapeutic potential for neuroregeneration and improved functional outcome. The pluripotent capacity of stem cells from the human umbilical cord blood provides simultaneous targeting of multiple neuropathologic events initiated by a hypoxic-ischemic insult. Their high regenerative potential and naïve immunologic phenotype makes them a preferable choice for transplantation. A multiplicity of transplantation protocols have been studied with a variety of brain injury models; however, only a few have been conducted on immature animals. Biological recipient characteristics, such as age and sex, appear to differentially modulate responses of the animals to the transplanted cord blood stem cells. Survival, migration, and function of the transplanted cells have also been studied and reveal insights into the mechanisms of cord blood stem cell effects. Data from preclinical studies have informed current clinical safety trials of human cord blood in neonates, and further work is needed to continue progress in this field.