It is now clear that functional p53 is critical to protect the genome from alterations that lead to tumorigenesis. However, with the myriad of cellular stresses and pathways linked to p53 activation, much remains unknown about how p53 maintains genome stability and the proteins involved. The current understanding of the multiple ways p53 contributes to genome stability and how two of its negative regulators, Mdm2 and Mdmx, induce genome instability will be described.