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The genetic and epigenetic events underlying cutaneous squamous cell carcinoma (SCC) have been actively studied; however, no resulting preventative or therapeutic strategies have successfully targeted this lesion, apart from surgery. In this issue of the JCI, two novel regulators of SCC pathogenesis are introduced, gain-of-function mutations in the p53 gene, reported by Caulin et al., and chemokine sequestration by the D6 receptor, reported by Nibbs et al. (see the related articles beginning on pages 1884 and 1893, respectively). These studies provide new twists and insights into the development of this potentially lethal disease.