Trp53 is a crucial sensor of cellular stress and a guardian of the genome. The tumor suppressor p53 is ubiquitously expressed in almost all cell types but is barely detectable under physiological conditions in unstressed cells. When a cell incurs various environmental or endogenous stresses, such as DNA damage, chemotoxin, oncogene activation, hypoxia, nutrient deprivation, replicative ribosomal stress, and viral infection, cellular p53 is activated causing an elevated level of p53 protein associated with its acetylation and phosphorylation. Activated p53 subsequently transactivates multiple molecular pathways, which induce apoptosis, senescence (a permanent non-reversible cell cycle arrest), or transient cell cycle arrest, depending on the level and nature of the stress, as well as the severity and reversibility of the damage that cells incur. Whereas severe stress and irreparable damage lead to apoptosis or senescence, modest stress and repairable damage cause transient cell cycle arrest for repair. The cell will re-enter the cell cycle to produce progeny once the damage is repaired. Thus, p53 plays an important role in ensuring proper health and function of all cells and is regarded as the caretaker, gatekeeper, and guardian of the genome.