The endoplasmic reticulum is the site of entry into the secretory pathway and represents a major and particularly crowded site of protein biosynthesis. In addition to the complexity of protein folding in any organelle, the ER environment poses further dangers and constraints to the process. A quality control apparatus exists to monitor the maturation of proteins in the ER. Nascent polypeptide chains are specifically prevented from traveling further along the secretory pathway until they have completed their folding or assembly. Proteins that cannot achieve a proper conformation are recognized and removed from the ER for degradation by the 26S proteasome. Finally, the homeostasis of the ER is vigilantly monitored and changes that impinge upon the proper maturation of proteins in this organelle lead to the activation of a signal transduction cascade that serves to restore balance to the ER. Recent studies suggest that some of these diverse functions may be achieved due to the organization of the ER into functional and perhaps even physical sub-domains.