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Cover   Understanding how cells generate structural and functional polarity is a fundamental problem at all levels of biology: from single-cell organisms such as bacteria and yeast, to tissues and organs in multicellular organisms. In multicellular organisms, simple epithelium form a single layer of cells that separates the "outside" from the "inside", and regulate ionic homeostasis by vectorial transport of ions and solutes between these compartments. Physiologists had long recognized that different ion transporters, channels and receptors are restricted to different plasma membrane domains, termed apical and basal-lateral, that face these compartments. However, mechanisms involved in generating the polarized cell surface distributions of these membrane proteins were unknown. In 1978, Rodriguez-Boulan and Sabatini published a landmark paper showing that different enveloped RNA viruses bud from either the apical or basal-lateral membrane domains of a cultured cell line derived from canine kidney epithelium. This cell line, termed Madin-Darby canine kidney (MDCK), had been isolated 20 years earlier by Madin and Darby, and subsequently characterized by Joseph Leighton and his colleagues. Rodriguez-Boulan and Sabatini showed that influenza virus budded specifically from the apical membrane of MDCK cells, whereas vesicular stomatitis virus (VSV) budded from the basal-lateral membrane. The cover reproduces electron micrographs from their paper showing polarized budding of influenza from the apical (top panel), but not basal-lateral membrane domain (bottom panel) of MDCK cells. Since the virally encoded envelope glycoproteins required for plasma membrane budding of these viruses [hemagglutinin (HA) of influenza, and G protein of VSV] were synthesized by the host MDCK cells, these observations implied that HA and G protein were sorted from each other at some stage of the secretory pathway and targeted to either the apical or basal-lateral membranes, respectively. Today, we generally know where, why, and, to a limited extent, how proteins are sorted to different membrane domains of simple epithelial cells. Although many details of these processes remain to be understood, these simple, elegant observations by Rodriguez-Boulan and Sabatini nearly 20 years ago revealed a tractable, experimental system that is used by many investigators to elucidate these mechanisms.W. James Nelson