In recent years, the gene defects causing many types of hereditary palmoplantar keratoderma have been discovered. These genes encode a variety of proteins involved in the terminal differentiation of keratinocytes and the formation of the cornified cell envelope. In this article, we review the molecular defects underlying various palmoplantar keratodermas with particular attention to the role of these molecules in the terminal differentiation of palmoplantar epidermis. Of the proteins involved in keratodermas, loricrin, keratins, and desmosomal proteins provide the protein structure of the cornified cell envelope. Connexins form intercellular gap junctions, which regulate ionic calcium signals necessary for the expression of the proteins that form the cornified cell envelope. Cathepsins likely mediate enzymatic processes necessary for the formation and dissolution of the cornified cell envelope. The clinical phenotypes produced by various mutations affecting these proteins are discussed vis-à-vis data from genetic, cellular, and molecular experiments. (J Am Acad Dermatol 2002;47:327-43.) Learning objective: At the completion of this learning activity, participants should be familiar with the genetic and molecular basis of hereditary palmoplantar keratodermas. The participants should also have more knowledge about the process of epidermal differentiation and formation and dissolution of the cornified cell envelope.