This chapter discusses the molecular basis of inherited diseases in which the primary changes are manifest in the skin and its appendages (nails, hair, sweat glands, and sebaceous glands). The disorders have been subdivided into sections according to their clinical presentation and molecular basis, but this is not a fixed classification, as many diseases will fit into more than one category. With increasing knowledge of the identities and functions of the genes involved in these inherited skin conditions, many of these disorders are being reclassified, as has occurred recently for epidermolysis bullosa (EB) and the ectodermal dysplasias. Molecular-based diagnostic criteria should help streamline the archaic and sometimes confusing classification systems currently in use. Knowledge of the precise molecular defect(s) underlying hereditary skin diseases will be a necessary step in the development and application of “personalized medicine” approaches to treatment, so that strategies targeting specific genes, pathways, or even mutant alleles may be possible in the near future.