The p53 pathway is inactivated in essentially all human tumors p53 is lost or mutated in over 50% of all human cancers, and the majority of the remaining tumors carry mutations in other components of the pathway. It appears that the main biological function of p53 in vivo is to suppress tumorigenesis, because mice with homozygous deletion of the p53 gene are normal, but develop multiple tumors at an early age. p53 plays a central role in cell cycle control and apoptosis in response to DNA damage and other stresses, and in response to oncogenic activation. Loss of p53 function leads to excessive proliferation due to an inappropriate cell cycle control, or to a reduced apoptosis and an excess survival. This allows propagation of cells with damaged DNA resulting in increased genetic instability and enhanced risk of cancer. The contribution of each of the p53 functions, or the lack thereof, to tumor initiation and progression has been studied in vivo, in genetically modified mice. Mice with deletions of one or both p53 alleles have been crossed with mice expressing dominant oncogenes, or lacking other tumor suppressor genes, in order to analyse the genetic interaction between different tumorigenic pathways in vivo. These studies have defined how oncogenic mutations can cooperate in tumorigenesis in tissue and the tumor-specific ways.