In contrast to the rapid progress made in the translation of genetic findings into new therapeutics in many other fields, major advances in our understanding of the pathogenesis of genetic skin diseases have not significantly changed the prospects for disease-targeted interventions. A major impediment to the development of new treatments for rare skin diseases stems from the lack of adequate models. Cell cultures can be derived from human sources but monolayers fail to capture the complexity of stratified epithelia. The development of three-dimensional skin cultures and the demonstration of their ability to reproduce both morphological and functional disease-related aberrations has revolutionized the approach to cutaneous disease modeling. To replicate monogenic disorders, current strategies involve either the use of patient-derived primary cells, whose supply is very limited, or the use of manipulated normal primary cells, which can be affected also in nonrelevant pathways. The recently discovered capacity of human somatic cells to be relatively easily reprogrammed into embryonic stem cell-like pluripotent stem cells offers numerous perspectives in therapies by providing patient-specific differentiated cells on demand. In the present application, we propose to develop a streamlined approach to the generation of human cellular models for monogenic skin diseases consisting of: (1) generation and characterization of induced pluripotent stem (iPS) cells from patients by cell reprogramming technology; (2) epidermal differentiation of iPS cells; (3) morphological, genetic, and functional validation of iPS cell-derived epidermal cells and generation of patient-specific three-dimensional skin models; (4) drug screening and therapy approaches using iPS cells as a perennial source of patient-derived epidermal cells; (5) characterization of gene targets and signaling pathways in animal models and validation of drugs.