The TP53 gene, encoding the tumour suppressor p53, is the most frequently altered gene in human cancer. Half of all cancers bear inactivating TP53 mutations, allowing cells to evade pro-apoptotic and cell cycle arrest signals leading to tumorigenesis. Melanoma is the most deadly form of skin cancer, due largely to the propensity of advanced disease to be highly chemo-refractory. Promising new treatments, such as BRAF inhibitors, are in advanced stages of clinical development, however early resistance to BRAF inhibition is commonly observed. In contrast to other human cancers, TP53 mutation in melanoma is rare (<5%). However, loss of p53 expression can cooperate with oncogenic NRAS and BRAF to promote melanomagenesis. Therefore, in this disease alternative mechanisms of p53 pathway suppression distinct from TP53 mutation may underlie tumorigenesis. We have found that MDM4, a negative regulator of p53, is significantly up-regulated in up to 68% of human melanomas, correlating with increased disease stage. Overexpression of MDM4 is observed equally in both BRAF mutant and wild-type melanomas. SAH-p53-8, a cell-permeable small peptide that binds with high affinity to the p53 binding pocket of MDM4, significantly inhibits xenograft melanoma tumour growth in vivo. Importantly, SAH-p53-8 effectively reduces cell viability in both BRAF inhibitor-sensitive and resistant melanoma cells, and co-treatment with SAH-p53-8 and BRAF-inhibitor synergistically act to kill melanoma cells. Therefore, strategies that inhibit MDM4/p53 interactions may be useful in the treatment of both BRAF-sensitive and -resistant melanomas, and potentially other human cancers, that exhibit MDM4-mediated p53 suppression.