A clinically and genetically heterogeneous group of disorders, known collectively as the palmoplantar keratodermas, are unified by the phenotypic characteristic of a thickening of the skin over the palms and soles. Although spectacular progress has been made in understanding the basis of many genodermatoses, the genetic defects causing many of the keratodermas are still largely unknown. These unusual phenotypes are beginning to capture the attention of investigators in epidermal biology, and several compelling lines of evidence point to the cornified cell envelope and structural components of the desmosome as potential underlying targets of disease. It is anticipated that understanding the molecular basis of the keratodermas will underscore the importance of the integrity of the cell envelope and the desmosome, and provide new insights into the mechanisms of epidermal differentiation and related disorders.