The genodermatosis epidermolysis bullosa (EB) is a monogenetic disease, characterized by severe blister formation on the skin and mucous membranes upon minimal mechanical trauma. Causes for the disease are mutations in genes encoding proteins that are essential for skin integrity. In EB, one of these proteins is either functionally impaired or completely absent. Therefore, the development and improvement of DNA and RNA-based therapeutic approaches for this severe blistering skin disease is mandatory to achieve a treatment option for the patients. Currently, there are several forms of DNA/RNA therapies potentially feasible for EB. Whereas some of them are still at the preclinical stage, others are clinically advanced and have already been applied to patients. In particular, this is the case for a cDNA replacement approach successfully applied for a small number of patients with junctional EB. The heterogeneity of EB justifies the development of therapeutic options with distinct modes of action at a DNA or RNA level. In addition, splicing-modulating therapies, based on RNA trans-splicing or short antisense oligonucleotides, especially designer nucleases, have steadily improved in efficiency and safety and thus likely represent the most promising gene therapy tool in the near future.