Although inactivating mutations or allelic loss of p53 are rare in melanomas, the p53 pathway is inactivated in the large majority of melanomas through a mechanism involving overexpression of negative regulators of p53: rarely by overexpression of MDM2 due to gene amplification, frequently (about 65%) by overexpression of MDM4 due to post-transcriptional mechanisms [82]. The gene discussed is MDM2; the disease is melanoma.