Surface epithelial cells, such as the epidermal keratinocyte, undergo a process of terminal cell differentiation that results in the construction of a multilayered epithelium. This epithelium functions to protect the organism from the environment. Transglutaminases, enzymes that catalyze the formation of isopeptide protein-protein cross-links, are key enzymes involved in the construction of this structure. This brief review will focus on the role of these enzymes in constructing the epidermal surface.