The outermost layer of the mammalian skin, the epidermis, forms a protective barrier against pathogenic microbes and tissue dehydration. This barrier is formed and maintained by complex genetic networks that connect cellular differentiation processes, enzymatic activities and cellular junctions. Disruption in these networks affects the balance between keratinocyte proliferation and differentiation resulting in barrier function impairment, epidermal hyperproliferation and in some cases, squamous cell carcinoma (SCC). Recent studies in wound-induced inflammation-mediated cancers in mice have identified dysregulation of core barrier components as tumor drivers. We therefore propose a hypothesis in which loss of key barrier genes, induce barrier dysfunction, and promote inflammation-driven epidermal hyperplasia and carcinogenesis over time. This emerging vision suggests that under specific genetic circumstances, localized barrier impairment could be considered as a hallmark of initiating lesions in epidermal SCC.