Production of a functional proteome is a major burden for our cells. Native proteins operate inside and outside the cells to eventually warrant life and adaptation to metabolic and environmental changes, there is no doubt that production and inappropriate handling of misfolded proteins may cause severe disease states. This review focuses on protein destruction, which is, paradoxically, a crucial event for cell and organism survival. It regulates the physiological turnover of proteins and the clearance of faulty biosynthetic products. It mainly relies on the intervention of two catabolic machineries, the ubiquitin proteasome system and the (auto)lysosomal system. Here, we have selected five questions dealing with how, why and when proteins produced in the mammalian endoplasmic reticulum are eventually selected for destruction.