The terminal differentiation of epithelial cells involves changes in the apical compartment, including remodeling of the cytoskeleton and junctions to modify its three-dimensional organization. It also often triggers the building of specialized extracellular matrices, the function of which remains poorly understood. Hundreds of extracellular matrix proteins expressed in a variety of epithelia possess a conserved region called the zona pellucida-domain (ZP domain). There is evidence to suggest that ZP-domains mediate the polymerization of proteins into fibrils or matrices and that mutation of ZP-domains can result in severe pathologies, such as infertility, deafness, and cancer. Recent work in worms and flies demonstrates that ZP-domain proteins play a crucial role in organizing and shaping highly specialized apical structures in epithelial cells.