Epidermolytic hyperkeratosis (EH; previously called bullous con al ichthyosiform erythroderma) is an autosomal dominant skin disease of unknown etiology, In the past year, transgenic mouse technology was utilized to infer the genetic basis for EBS, which involves mutations in one of two genes encoding basal-specific epidermal keratins K5 and K14 (5, 6). Transgenic mice expressing mutant K14 genes exhibited EBS phenotypes (5, 6), and subsequent analyses ofhuman EBS patients revealed mutations in the K5 and K14 genes (7-9). As epidermal cells commit to terminally differentiate, they switch off K5 and K14 expression and switch on a new set of keratins, K1 and K10 (10-14). In the fully differentiated squame, K1 and K10 (in slightly processed forms) constitute -85% of cellular protein (10). Given (i) the parallels between tonofilament clumping in EH and EBS, (ii) the knowledge that EBS is a keratin disorder, and (iii) the pattern of keratin expression during differentiation, we utilized transgenic technology to investigate the possibility that EH is a genetic disease involving K1 and K10 defects.