Epidermolysis Bullosa Simplex (EBS) is a genetic disorder usually characterized by an autosomal dominant mode of transmission in which the skin blisters in response to trivial mechanical trauma. There are several clinical variants of EBS, ranging from clinically mild to very severe and even lethal, but in all cases the primary lesion responsible for the blistering is trauma-induced lysis of the epidermal basal layer. Epidermal basal cells normally feature an extensive cytoplasmic network of 10 nm filaments made of keratins K5 and K14, and the architecture of this network is often perturbed in the epidermis of EBS patients. The recent advent of a variety of molecular genetic techniques has allowed us to study the effects of perturbing the keratin filament network in epidermal cells in situ, and test the possible implications for EBS. Thus, targeted expression of K14 mutants which disrupt 10 nm-filament assembly in the epidermal basal layer of transgenic mice causes a phenotype mimicking EBS remarkably well, suggesting that at least some cases of EBS might arise as a result of mutations in basal-specific keratin genes. Indeed, point mutations in either the K5 or K14 coding sequence have recently been discovered in several incidences of EBS, and compelling evidence that these mutations are indeed responsible for the disease has been provided. These recent findings and their implication for the function of 10 nm keratin filaments in epidermis are discussed in this article.