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About half of patients with the blistering skin disorder recessive dystrophic epidermolysis bullosa caused by mutations in collagen VII are predisposed to developing epidermal cancers, whereas the remainder are not. In their Perspective, Yuspa and Epstein discuss new findings ( Ortiz-Urda et al.) that reveal the reason for this paradox. The ability of keratinocytes from these patients to become tumorigenic depends on whether the patients carry a collagen VII mutation that results in production of collagen VII containing the crucial NC1 domain. Keratinocytes from patients who carry a mutation that blocks production of collagen VII do not become tumorigenic.