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Loss of cell polarity and tissue disorganization occurs in majority of epithelial cancers. Studies in simple model organisms identified molecular mechanisms responsible for the establishment and maintenance of cellular polarity, which play a pivotal role in establishing proper tissue architecture. The exact role of these cell polarity pathways in mammalian cancer is not completely understood. Here we analyzed the mammalian orthologs of drosophila apical-basal polarity gene lethal giant larvae (lgl), which regulates asymmetric stem cell division and functions as a tumor suppressor in flies. There are two mammalian orthologs oflgl(Llgl1andLlgl2). To determine the role of the entire lgl signaling pathway in mammals we generated mice with ablation of bothLlgl1andLlgl2in skin epidermis using K14-Cre (Llgl1/2-/-cKO mice). Surprisingly, we found that ablation ofLlgl1/2genes does not impact epidermal polarity in adult mice. However, oldLlgl1/2cKO mice present with focal skin lesions which are missing epidermal layer and ripe with inflammation. To determine the role of lgl signaling pathway in cancer we generatedTrp53-/-/Llgl1/2-/-cKO andTrp53-/+/Llgl1/2-/-cKO mice. Loss ofLlgl1/2promoted squamous cell carcinoma (SCC) development inTrp53-/-cKO and caused SCC inTrp53-/+cKO mice, while no cancer was observed inTrp53-/+cKO controls. Mechanistically, we show that ablation ofLlgl1/2causes activation of aPKC and upregulation of NF-kB signaling pathway, which may be necessary for SCC inTrp53-/+/Llgl1/2-/-cKO mice. We conclude that Lgl signaling pathway functions as a tumor suppressor in mammalian skin epidermis.