The process of differentiation in keratinocytes of human buccal mucosa is accompanied by a number of specific membrane and cytoplasmic changes. Using simple tissue culture techniques, it has been possible to establish an in vitro model for keratinocyte differentiation which closely resembles the in vivo situation. A multi-layered structure is formed with maturation towards the surface. The superficial cells are characterized by a thickening of the plasma membrane, an increased concentration of tonofilaments, loss of intercellular adhesions and the presence of membrane-coated granules. It is concluded that this represents a suitable in vitro model for the biological and pathological study of both normal and abnormal oral epithelium.