The first terrestrial vertebrates emerged from water and adapted to living on land approximately 360 million years ago (late Devonian). In particular, amphibians are thought to have surface epithelia that changed from multilayered epithelia into keratinized stratified squamous epithelia by acquiring stratum corneum (SC), which is composed of several dead cell layers that serve as an air liquid interface barrier. Then, reptiles appeared and became a major terrestrial vertebrate group approximately 340 million years ago by forming hard SC. About 220 million years ago, mammals radiated by acquiring soft and moisturized SC, and endogenous retroviruses were thought to be actively integrated into mammalian genomes. Skin ASpartic Protease (SASPase)/ASPRV1 is the mammalian-specific endogenous retroviral-derived protease. SASPase-deficient mice had dry skin and aberrant accumulation of profilaggrin, which is another mammalian-specific gene that regulates SC barrier function and is a major predisposing factor for atopic dermatitis. These findings indicate that the retroviral element SASPase was integrated into the first mammalian species and was involved in the adaptive evolution of mammals, as it facilitates moisturization of skin SC. It is possible that other uncharacterized endogenous retroviruses were also involved in epidermal barrier function.