FBXW7 is a tumor suppressor gene and is responsible for ubiquitination and turnover of several oncoprotiens. Loss-of-function mutations of FBXW7 lead to constitutive NOTCH1 pathway activation via inhibition of ubiquitin-mediated degradation of activated NOTCH1 and MYC. FBXW7 mutations have been reported in ~3-8% of melanomas. Preclinical data suggest that FBXW7 mutations sensitize cells to mTOR inhibitors. However, advanced tumors with somatic FBXW7 mutations and other concurrent molecular alterations might have limited therapeutic response to mTOR inihibitors. Correlation with other clinical and laboratory findings is recommended.