Leading the way in imposing a policy of zero tolerance of cellular abnormalities that might lead to tumor development is the p53 protein. The efficiency of p53 in preventing cell growth is a strong deterrent to malignant progression, but this activity must be kept tightly restrained to allow normal cell growth and development. Essential components of this regulation are the mechanisms by which the p53 protein is degraded, and efficient turnover of p53 in normal cells prevents the accumulation of the protein. Modulation of these degradation pathways in response to stress leads to the rapid stabilization and accumulation of p53, and activation of the p53 response. It is now becoming clear that the Mdm2 protein is central to the regulation of p53 stability and multiple pathways exist through which the activity of Mdm2 can be inhibited. Defects in the ability to stabilize p53 are likely to contribute to malignant development, and restoration of this activity represents an extremely attractive possibility for tumor therapy.