Herein, our results obtained using immunocompetent transgenic mice show that a moderate increase in the wild type CYLD expression levels prevents the development and progression of skin squamous cell tumors, mainly through the attenuation of NF-κB activation, reduction of tumor proliferation, increased tumor cell differentiation, and inhibition of both tumor inflammation and angiogenesis. This evidence concerns the gene NFKB1 and neoplasm.