Unfolded and misfolded proteins are inherently toxic to cells and have to be quickly and efficiently eliminated before they intoxicate the intracellular environment. This is of particular importance during proteotoxic stress when, as a consequence of intrinsic or extrinsic factors, the levels of misfolded proteins are transiently or persistently elevated. To meet this demand, metazoan cells have developed specific protein quality control mechanisms that allow the identification and proper handling of non-native proteins. An important defence mechanism is the specific destruction of these proteins by the ubiquitin-proteasome system (UPS). A number of studies have shown that various proteotoxic stress conditions can cause functional impairment of the UPS resulting in cellular dysfunction and apoptosis. In this review, we will summarize our current understanding of proteotoxic stress-induced dysfunction of the UPS and some of its implications for human pathologies.