Integrins are heterodimeric transmembrane glyco-proteins which are engaged in a variety of cellular functions, such as adhesion, migration and differentiation¹. The integrin α6β4 is expressed on squa-mous epithelia², on subsets of endothelial cells³, immature thymocytes⁴ and on Schwann cells and fibroblasts in the peripheral nervous system⁵. In stratified epithelia, α6β4 is concentrated in specialised adhesion structures, called hemidesmosomes^6,7, which are implicated in the stable attachment of the basal cells to the underlying basement membrane by connecting the intermediate filaments with the extracellular matrix⁸. The nature of the interactions between the various hemidesmosomal proteins, that lead to the formation of hemidesmosomes is poorly understood. To study the contribution of the integrin α6β4 in hemidesmosome formation and their anchoring properties, we inactivated the β4 gene in mice by targeted gene disruption. Homozygous β4 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.