Brain injury resulting from perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of acute mortality in infants and chronic neurologic disability in surviving children. Recent multicenter clinical trials demonstrated the effectiveness of hypothermia initiated within the first 6 postnatal hours to reduce the risk of death or major neurological disabilities among neonates with HIE. However, in these trials, approximately 40% of cooled infants died or survived with significant impairments. Therefore, adjunct therapies are required to improve the outcome in neonates with HIE. Cord blood (CB) is a rich source of stem cells. Administration of human CB cells in animal models of HIE has generally resulted in improved outcomes and multiple mechanisms have been suggested including anti-inflammation, release of neurotrophic factors and stimulation of endogenous neurogenesis. Investigators at Duke are conducting studies of autologous CB infusion in neonates with HIE and in children with cerebral palsy. These pilot studies indicate no added risk from the regimens used, but results of ongoing placebo-controlled trials are needed to assess efficacy. Meanwhile, further investigations are warranted to determine the best strategies, that is, timing, dosing, route of delivery, choice of stem cells and ex vivo modulations, to attain long-term benefits of CB stem cell therapy.