The outer part of the skin, the epidermis, is specialized to protect the human body from its environment. Because of the high levels of physical stress experienced by the human hand in everyday use, the epidermis of the hand is especially toughened. In particular, the epidermis of the palm is highly specialized to resist mechanical trauma. Like the epidermis, the nails are composed of specialized epithelial cells and are especially strong. In recent years it has become apparent that the physical strength of epithelial cells comes from the keratin cytoskeleton--a dense meshwork of filaments extending throughout the cytoplasm. Keratins are a large family of intermediate filament proteins encoded by more than 50 distinct genes in humans. These different keratin genes are expressed in well-defined combinations in specific epithelial tissues. Several keratin genes are expressed in palmoplantar epidermis and in the stratified epithelia of the nail bed. Genetic mutations in these genes lead to fragility of these tissues and result in a range of genetic disorders characterized by blistering and thickening of palm and sole skin and/or nails. Study of these diseases has shed new light on the vital structural role of keratins in maintaining the integrity of epithelial cells.