Epidermolytic ichthyosis (EI) is a skin fragility disorder caused by dominant-negative mutations in KRT1 or KRT10. No definitive restorative therapies exist that target these genetic faults. Gene editing can be used to efficiently introduce frameshift mutations to inactivate mutant genes. This can be applied to counter the effect of dominantly inherited diseases, such as EI. In this study, we utilised transcription activator-like effector nuclease (TALEN) technology, to disrupt disease-causing mutant KRT10 alleles in an ex vivo cellular approach, with the intent of developing a therapy for EI patients. TALENs were designed to specifically target a region of KRT10, upstream of a premature termination codon known to induce a genetic knockout. These proved highly efficient at gene disruption in a patient-derived keratinocyte cell line. Additionally, analysis for off-target effects indicated no promiscuous TALEN-mediated gene disruption. Reversion of the keratin intermediate filament fragility phenotype associated with EI was observed by immunoflourescence analysis of TALEN-treated and correctly modified single cell clones, in concurrence with immunoflourescence and ultrastructure analysis of murine xenograft models. The efficiency of this approach was subsequently confirmed in primary patient keratinocytes. Our data demonstrates the feasibility of an ex vivo gene editing therapy for more than 95.6% of dominant KRT10 mutations.