The past years have witnessed dramatic advances in our understanding of the way genetic defects cause disease manifestations. While in the past, a specific genetic defect was expected to always give rise to the same clinical phenotype, it is today clear that environmental factors, epigenetic changes and co-inherited genetic variations can significantly affect the phenotypic expression of pathogenic variants driving disease manifestations. Modifiers of all three types have been identified in a wide range of skin diseases, including blistering disorders, ichthyoses and hair diseases. Phenotypic modification is not only of relevance to the genetic counseling of families at risk for genodermatoses, they may also point at novel therapeutic targets for these as well as more common diseases.