Epithelial organs consist on layers of cubical cells that separate different compartments. They form a physical barrier that allows the regulated transports of certain molecules and ions. To perform this and other functions epithelial cells require to be highly polarized. The molecular mechanisms that integrate cellular polarity with epithelial architecture are poorly understood. Using a three-dimensional model of epithelial morphogenesis, we have recently reported a molecular mechanism for the formation of the apical membrane and the central lumen.(1) This molecular pathway is initiated by the membrane segregation of phosphoinositides at the apical domain. Apically localized phosphatidylinositol(4,5)-bisphosphate [PtdIns(4,5)P2] recruits the scaffolding protein Annexin2 and the GTPase Cdc42 to generate the apical plasma membrane domain and the central lumen.