Follow-up studies have shown that the vast majority of neurological abnormalities present during childhood can have a prenatal or perinatal origin. It is relevant, therefore, to investigate the timing of adverse insults in the search for measures of prevention. However, such knowledge is still incomplete and subject to debate. Until recently, clinical-laboratory assessment was based essentially on biochemical aspecific parameters, ultrasound and Doppler patterns, and the determination of blood pH and gases. However, the measurement of brain constituents may offer a direct indicator of cell damage in the nervous system. The S100B protein, a calcium-binding protein highly concentrated in the nervous system, appears to meet the criteria required of such a marker in prenatal and perinatal medicine for its reproducible, simple and sensible measurements. Results in high-risk pregnancies demonstrated that S100B concentration increased in amniotic fluid and in cord blood of fetuses with brain damage. In addition, S100B protein has been also usefully employed to monitor the effects of maternal-antenatal therapy, such as NO and glucocorticoid administration. It appears also to be relevant that a neurotrophic role has been hypothesized for the protein, which in fact exhibits in amniotic fluid, in cord blood and in placenta patterns of concentration related to the gestational age.