Since its discovery 25 years ago, the p53 protein has emerged as a key tumor suppressor protein at the crossroads of cellular stress response pathways. Through these pathways, which can lead to cell-cycle arrest, DNA repair, cellular senescence, differentiation and apoptosis, p53 facilitates the repair and survival of damaged cells or eliminates severely damaged cells from the replicative pool to protect the organism. Because of these dynamic and multiple functions of p53, which are largely lost following mutations in the gene encoding p53, this molecule continues to be studied intensively in biomedical research, including the fields of toxicology and pharmacology. In this article, we briefly review the first 25 years of research on p53.