The p53 gene is required for the normal apoptotic response of mammalian cells to DNA damage caused by ionizing radiation and DNA damaging drugs. DNA damage results in the accumulation of biologically active p53. This response is potentially lethal and is therefore highly regulated. By using both biochemical and cell biological approaches a number of discrete control pathways have been identified. These include analysis of cellular and viral proteins that bind to p53 to inactivate its function, the discovery of cells with defects in the p53 activation pathway and the analysis of an allosteric regulation of p53 function controlled by phosphorylation.