THE TOPOLOGICAL BARRIERS DEFINED BY BIOLOGICAL MEMBRANES ARE NOT IMPERMEABLE: from small solutes to intact proteins, specialized transport and translocation mechanisms adjust to the cell's needs. Here, we review the removal of unwanted proteins from the endoplasmic reticulum (ER) and emphasize the need to extend observations from tissue culture models and simple eukaryotes to studies in whole animals. The variation in protein production and composition that characterizes different cell types and tissues requires tailor-made solutions to exert proper control over both protein synthesis and breakdown. The ER is an organelle essential to achieve and maintain such homeostasis.