The differentiation program followed by the epidermal keratinocyte in skin is intended to continuously produce and maintain a cornified layer made of fully keratinized cells. This outer layer of the body provides a certain protection against external pathogens and chemical or physical agents, together with a barrier that prevents loss of body fluids. Considerable knowledge of epidermal differentiation and understanding of its regulation has progressively emerged from the availability of keratinocyte cultures, and from the consecutive possibility of unlimited in vitro experimentation. This short review briefly presents the main current in vitro models of epidermal differentiation and emphasises their advantages of pitfalls when studying particular steps of the differentiation program or analyzing their regulation.