Integrins are heterodimeric transmembrane glycoproteins which are engaged in a variety of cellular functions, such as adhesion, migration and differentiation1. The integrin alpha 6 beta 4 is expressed on squamous epithelia, on subsets of endothelial cells, immature thymocytes and on Schwann cells and fibroblasts in the peripheral nervous system. In stratified epithelia, alpha 6 beta 4 is concentrated in specialised adhesion structures, called hemidesmosomes, which are implicated in the stable attachment of the basal cells to the underlying basement membrane by connecting the intermediate filaments with the extracellular matrix. The nature of the interactions between the various hemidesmosomal proteins, that lead to the formation of hemidesmosome is poorly understood. To study the contribution of the integrin alpha 6 beta 4 in hemidesmosome formation and their anchoring properties, we inactivated the beta 4 gene in mice by targeted gene disruption. Homozygous beta 4 null mice died shortly after birth and displayed extensive detachment of the epidermis and other squamous epithelia. The dramatically reduced adhesive properties of the skin was accompanied by the absence of hemidesmosomes at the basal surface of keratinocytes. No evidence was found for impaired T-cell development, nor for defects in myelination in the peripheral nervous system.