The endoplasmic reticulum (ER) is a highly organized and specialized organelle optimized for the production of proteins. It is comprised of a highly interconnected network of tubules that contain a large set of resident proteins dedicated to the maturation and processing of proteins that traverse the eukaryotic secretory pathway. As protein maturation is an imperfect process, frequently resulting in misfolding and/or the formation of aggregates, proteins are subjected to a series of evaluation processes within the ER. Proteins deemed native are sorted for anterograde trafficking, while immature or non-native proteins are initially retained in the ER in an attempt to rescue the aberrant products. Terminally misfolded substrates are eventually targeted for turnover through the ER-associated degradation or ERAD pathway to protect the cell from the release of a defective product. A clearer picture of the identity of the machinery involved in these quality control evaluation processes and their mechanisms of actions has emerged over the past decade.