Many types of adult stem cells have been used in pre-clinical situations to treat experimental hypoxic-ischemic (HI) injury in neonatal animals. Numerous laboratory reports have appeared in the literature indicating that this treatment is beneficial, and the route of cell administration does not appear to be critical. The success of treatment occurs with administration soon after the injury, and this early administration of the cells proximate to the time of injury appears to be decisive. The mechanism of benefit relates to preservation of intrinsic neurons at the site of injury rather than cell replacement by the administered cells. There are few clinical studies, and most positive reports are either from uncontrolled studies or anecdotal. Given the preclinical success with treatment, well-thought-out clinical studies need to be initiated in acutely brain injured neonates.