The skin is the largest organ of the human body, and is the home of constant cycles of exquisitely regulated cell migration, differentiation, and regeneration. In stratifying squamous epithelia, such as the skin, the cornified cell envelope (CE), a highly insoluble peripheral layer of crosslinked proteins, replaces the plasma membrane in a complex and sequential fashion from precursor proteins initially dispersed in the cytoplasm. The insolubility of the CE is based on the presence of N-ε(γ-glutamyl) lysine isodipeptide cross-links formed by epidermal transglutaminases. Because of its mechanical resilience and impenetrability, the CE provides the human skin with a protective barrier against the environment. Here, we provide an overview of the different components of the CE and their properties and function within this complex scaffolding of cross-linked proteins.