Heritable forms of epidermolysis bullosa (EB), a heterogeneous group of skin fragility disorders, manifest with blistering and erosions with high degree of morbidity (1–3). The phenotypic spectrum is highly variable, and in the most severe cases the patients die within the early postnatal period or within a few months of life due to complications of fragile skin, such as infections, sepsis, dehydration, and metabolic alterations. Some of these cases are also associated with extracutaneous manifestations in the syndromic forms of EB, affecting the lungs, kidneys, and heart (4). There is no effective treatment for EB. In PNAS, Jack ´ow et al. (5) report on a CRISPR/ Cas9-mediated therapy approach for a form of EB. Critical for understanding the molecular basis of EB is the recognition of adhesion complexes consisting of interacting proteins, which form a network responsible for keratinocyte cell–cell adhesion and stable association of the epidermis and the underlying dermis (Fig. 1). Currently, there are 21 distinct genes that have been demonstrated to harbor mutations in different forms of EB (6, 7). The topographic location of the mutant genes within the epidermis and the cutaneous basement membrane zone, the types and combinations of the mutations, and their consequences at the mRNA and protein levels collectively explain the tremendous phenotypic variability in this group of disorders.