As the importance of p53 in CNS development and cancer has been extensively reviewed previously [15,17,18], this article primarily reviewed studies published during 2005– August of 2020, along with a number of major p53 researches reported more than 15 years ago, which investigated p53′s functions in brain development and neural stem cell regulation, as well as p53 inactivation and its underlying mechanisms in brain tumors (Figure 1). Here, TP53 is linked to cancer.