The increased MDM4 expression in melanoma has pathological implications, as shown by several observations: (a) MDM4 protein expression was either undetectable or very low in normal melanocytes and in benign nevi; (b) MDM4 overexpression cooperates with NRAS mutation in inducing melanoma development in experimental models; (c) MDM4 overexpression promotes the survival of melanoma cells and the inhibition of the MDM4–p53 interaction restores p53 function in melanoma cells, resulting in increased sensitivity to standard cytotoxic therapy and to BRAF inhibitors [82]. This evidence concerns the gene MDM4 and melanoma.