Recent studies are delineating a detailed picture of the architecture and function of the endoplasmic reticulum (ER) and the early secretory pathway, showing the existence of dynamic compartmentalization of ER quality control and ER-associated degradation (ERAD) factors. The compartmentalization is regulated by ER protein load and in turn regulates protein processing and cell fate. This compartmentalization is intimately linked to the protein quality control processes, protein disposal through ERAD, the unfolded protein response, and the initiation of apoptosis. It includes novel compartments, the ER-derived quality control compartment (ERQC), vesicles implicated in "ERAD-tuning," and the mitochondria-associated membranes (MAMs).