At the beginning of the 21st century, the role of p53 as a tumor suppressor was well established; however, the function of p53 other than tumor suppression, especially its function under physiological conditions, was poorly understood. Here, we revisited the journey of a multidisciplinary team of researchers that revealed an unexpected and important function of p53 in regulating maternal reproduction at that time. This finding of p53 in maternal reproduction helped us gain important insights about the p53 protein and expanded our understanding of p53 protein functions in addition to its tumor suppressive function. This finding also provided a possible clue to explain the observed evolutionary selection on some alleles of the p53 pathway.