Birth asphyxia results in a significant percentage of neonatal morbidity and mortality. A key factor in the management of this complication is the early and accurate detection of brain damage following asphyxia. Currently, reliable tools for such diagnosis are absent. Extensive research has focused on biomarkers in an attempt to solve this matter. Recent data marked serum and urine elevation of the S100B protein as an established peripheral biomarker for detection of brain injury including traumatic head injuries and brain damage following cardiac arrest and stroke. In the past decade, a substantial number of studies illustrated the potential use of S100B testing in order to detect brain damage in asphyxiated newborns. This review summarizes the available data regarding the use of S100B as a biomarker of brain damage following birth asphyxia.