A large number of mutations in keratin genes underlie inherited tissue fragility disorders of epithelia. The genotype-phenotype correlations emerging from these studies provide a rich source of information about the function of keratins that would have taken decades to achieve by a purely transgenic approach. Human disease studies are being supplemented by engineered mouse mutant studies, which give access to the effects of genetic alterations unlikely to occur naturally. Evidence is emerging that the great diversity of keratins might be required to enable cells to adapt their structure in response to different signalling pathways.