p53 is well known for its key role as a tumor suppressor protein. It is 393 amino acids (aa) in length with a predicted molecular weight of 44 kDa. It belongs to the p53 family that also includes p63 and p73. Structurally, p53 is characterized by an N-terminal transactivation domain, central DNA-binding and oligomerization domains, and a C-terminal regulatory domain. It is thought to exist as a homotetramer, and it exhibits approximately 72% and 76% aa identity with its mouse and rat orthologs, respectively. Mutations in the p53 gene are one of the most frequent genomic events accompanying oncogenic transformation. p53 responds to signals such as DNA damage or cell stress primarily through its actions as a transcription factor. Among its gene targets are a range factors that promote DNA repair mechanisms or cancer, including cell cycle regulatory proteins and members the Bcl-2 family. Because of its critical role in genomic homeostasis, p53 activities are tightly regulated by a network of protein-protein interactions, microRNAs, and a range of post-translational modifications, including phosphorylation, acetylation, methylation and ubiquitination. The stability of p53 is regulated via the ubiquitin-proteasome pathway (UPP). MDM2 is an oncogenic ubiquitin E3 ligase that ubiquitinates p53, inhibits its transcriptional activity and promotes its degradation. Other E3 ligases that promote the proteasome-mediated degradation of p53 include Pirh2, COP1 and p300. USP7 (HAUSP) stabilizes p53 by deubiquitination and induces p53-dependent cell growth repression and cancer. Additional factors such as p14ARF and MdmX also modulate p53 function via the UPP.