This chapter focuses on the synthesis and transport of the secreted proteins. Constitutive secretion is characterized by the rapid exocytosis of newly synthesized proteins. The Endoplasmic Reticulum (ER) of secretory cells is made up of an extensive network of ribosome-studded, so-called rough-surfaced, membranes. Studies of yeast and mammalian cells have contributed considerably to our understanding of how proteins are targeted to the endomembrane system and sorted into different pathways of the secretory system. Unraveling the details of protein translocation into the ER lumen has highlighted interesting differences and similarities among eukaryotes. At least two ideas have been advanced to explain how the soluble reticuloplasmins are retained in the ER lumen. One proposal invokes the formation of a meshwork of proteins that are cross-linked into an immobile complex; the other postulates the interaction of the XDEL tetrapeptide with a receptor in the salvage compartment of the secretory pathway.