All epithelia form sheets of cells connected by tight and adherent junctions and exhibit polarized distribution of membrane proteins and lipids. During their development, epithelia progress from this 'generic' phenotype to terminally differentiated states characterized by the development of apical structures such as microvilli, apical endocytosis and regulated exocytosis as well as characteristic cell shapes. We have identified an extracellular matrix protein, hensin, which when polymerized into a fiber induces the terminal differentiation of renal cells. Hensin is expressed in most epithelia where it exists in tissuespecific alternately spliced forms. Many epithelial tumors have deletions in the human ortholog of hensin. We propose that hensin mediates terminal differentiation of these epithelia.