This review assesses molecular aspects of the rescue of disease-causing mutations in genodermatoses by means of naturally occurring secondary genetic phenomena. Such data have important implications for the design of gene therapy approaches for inherited skin diseases. Reversal of the phenotype depends on three elements: the number of cells involved; the degree of gene reversal; and the specific timing of the reversion. If reversion occurs in somatic cells, revertant mosaicism may occur. This is the situation in which a patient's skin is generally affected by the genodermatosis, but islands of normal skin stand out. These reflect the presence of revertant cells that are sufficient to restore a normal local skin phenotype. Reversion of the original mutation may also be partial, in which case the phenotype may display no, or only limited, improvement. Nevertheless, the phenotype may ameliorate with age if the reverted cells preferentially expand in time or if the time of onset of reversion is after birth. In essence, the complexities of naturally occurring rescue processes are important to understand because the inherent mechanisms may provide clues and insight into optimal therapeutic gene manipulation, and the possibility of mimicking nature in the management of patients with diverse genodermatoses.