Since p53 was cloned and subsequently characterized as a tumor suppressor more the 20 years ago, more than 40,000 publications have been published relating to this protein. A great majority of this scientific literature focuses on the intricate details of p53 regulation by posttranslational modifications. Phosphorylation, the first posttranslational modification of p53 identified, was established as a positive regulator of p53 via modification at multiple sites by an ever-growing number of kinases activated by numerous stress signals. Subsequently, acetylation and ubiquitination have been established as major regulators of p53 by regulating p53 transcriptional activity and stability, respectively. More recently, other modifications, such as sumoylation, neddylation, methylation, and glycosylation, have been reported. Although the cellular effects of many modifications are established, mouse models using site-specific knockin approaches imply that some of these modifications are to some degree redundant. These findings raise the possibility that aspects of the p53 posttranslational regulatory network are redundant yet indispensable for exact and precise control of p53 activity upon stress-induced stimulation.