A variety of skin equivalent systems have been developed recently mainly for burn therapy but also for studies of the cell and molecular biology of dermatologic and immunologic disorders and for cosmetic and pharmaceutical research. Since European regulation forbids the use of animals to prove product safety in cosmetic products, several commercially available three-dimensional skin models were developed by the cosmetic and chemical industry and validated according to OECD and ECVAM regulations. Three-dimensional skin models consist of two compartments: one serves as a dermal equivalent, usually consisting of fibroblasts in type I collagen, onto which a terminally differentiating epidermis is placed. Up-to-date models are missing that mimic monogenic skin disorders or signs of disease in the skin caused by a systemic autoimmune disorder. We recently developed a three-dimensional skin model for congenital ichthyosis as an example for a keratinization disorder. The system is being validated and will be fundamental for studies of disturbed epidermal differentiation and pharmaceutical intervention.