This article reviews the recent molecular and clinical studies that characterize the role of p53 in pathologies of the central nervous system, p53 has many important biological functions, notably, maintenance of DNA stability and regulation of apoptosis. These features are essential to avoid cellular transformation and ensure normal brain development. Lack of p53 function in the brain results in tumor formation in the astrocytic and lymphoid lineages and in severe neurodevelopmental diseases, such as exencephaly.