With increasing pressure on biomedical research to focus on issues that affect the widest number of people, the study of rare diseases is often at risk of loosing financial support. However rare diseases can be hugely informative for normal biological processes. Monogenic diseases present us with genetically-driven pathology arising from a single mutation, that can point unambiguously to the function of a single gene and its widespread consequences. One such area is the rare diseases arising from mutations in intermediate filament proteins, a large family of major structural cytoskeleton elements found in all tissues. Their function was poorly understood before these genes were identified as underlying many forms of tissue malfunction, often tissue fragility. The earliest example came from the epidermis, in which point mutations in keratins K5 and/or K14 lead to the skin fragility disorder known as epidermolysis bullosa simplex (EBS), a disorder in which the epidermis blisters upon quite mild physical trauma. We are using EBS and other rare disorders to understand keratin function and regulation in normal epithelia and its altered regulation in tissue stress. Using disease-mimetic experimental model systems one can better understand both EBS and epidermal wound responses, possibly identifying new and financially practical approaches to EBS therapy.