The endoplasmic reticulum (ER) is the site of maturation for roughly one-third of all cellular proteins. ER-resident molecular chaperones and folding catalysts promote folding and assembly of this diverse set of newly synthesized proteins. As these processes are error-prone, all eukaryotic cells have a quality control system in place that constantly monitors the proteins and decides their fate. Proteins with potentially harmful non-native conformations are subjected to assisted-folding or degraded. Persistent folding-defective proteins are distinguished from folding intermediates and targeted for degradation by a specific process involving clearance from the ER. Although the basic principles of these processes appear conserved from yeast to animals and plants, there are distinct differences in the ER-associated degradation of misfolded glycoproteins. The general importance of ER quality control events is underscored by their involvement in biogenesis of diverse cell surface receptors and the crucial function to maintain protein homeostasis under diverse stress conditions.