All proteins in a cell continuously turn over, each at its own rate, contributing to a cell's development, differentiation, or aging. Of course, unnecessary protein(s), or those synthesized in excess, that hamper cellular homeostasis should be discarded rapidly. Furthermore, cells that have been subjected to various environmental stresses, e.g., reactive oxygen species (ROS) and UV irradiation, may incur various types of protein damage, which vitiate normal and homeostatic functions in the cell. Thereby, the prompt elimination of impaired proteins is essential for cell viability. This housekeeping is accomplished by two major catabolic routes—proteasomal digestion and autophagy. Strict maintenance of proteostasis is particularly important in non-proliferative cells, especially neurons, and it is plausible that its failure leads to a number of the neurodegenerative diseases becoming prominent in the growing elderly population. This article is part of a Special Issue entitled: Ubiquitin–Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf.