Cell-extracellular matrix interactions have important roles in many biological processes, including embryonic development, growth control and differentiation. Integrins are the principal receptors for extracellular matrix. They are composed of non-covalently associated alpha and beta chains. Integrin alpha 6 can associate with either beta 1 or beta 4 (refs 2,3). Both integrin complexes are receptors for laminins, major components of basement membranes. The distribution of alpha 6 (refs 4-10) as well as studies using function-blocking antibodies have suggested an essential role for this laminin receptor during embryogenesis, in processes such as endoderm migration or kidney tubule formation9. Here we report that, surprisingly, mice lacking the alpha 6 integrin chain develop to birth. However, they die at birth with severe blistering of the skin and other epithelia, a phenotype reminiscent of the human disorder epidermolysis bullosa. Hemidesmosomes are absent in mutant tissue. This absence is likely to result from the lack of alpha 6/beta 4, the only integrin in hemidesmosomes of stratified squamous and transitional epithelia. Mutations in the genes encoding integrin beta 4 and chains of laminin-5 have been implicated in junctional epidermolysis bullosa. Our study provides evidence that some forms of epidermolysis bullosa may originate from defects of the alpha 6 gene.