In mammalian cells, the endoplasmic reticulum orchestrates the folding and assembly of nearly one-third of the mammalian proteome. Proper protein folding is essential for cell survival and function and is mediated by a dynamic ER quality control system that ensures the final polypeptide product meets the needs of the cell. If the folding of a protein does not reach its native conformation, it will be selected for ER-associated degradation (ERAD) to prevent aggregation of misfolded proteins and potential proteotoxic effects. Recent work in our lab has begun to elucidate the physiological significance of ERAD in health and disease by revealing novel cell-type specific roles. This includes the role of ERAD in mediating the maturation of prohormones in the paraventricular hypothalamus, the maintenance of exocrine pancreatic function, and the management of systemic lipid metabolism. Given the broad role of ERAD in mammalian physiology, a critical gap remains in determining how ERAD can recognize and regulate different substrates in a cell-type specific manner. My current interest is to explore how different ERAD complexes and regulatory components can fine-tune substrate specificity to help manage the large and diverse mammalian secretory proteome.