Maintaining cellular redox status to allow cell signalling to occur requires modulation of both the controlled production of oxidants and the thiol-reducing networks to allow specific regulatory post-translational modification of protein thiols. The oxidative stress hypothesis captured the concept that overproduction of oxidants can be proteotoxic, but failed to predict the recent finding that hyperactivation of the KEAP1-NRF2 system also leads to proteotoxicity. Furthermore, sustained activation of thiol redox networks by KEAP1-NRF2 induces a reductive stress, by decreasing the lifetime of necessary oxidative post-translational modifications required for normal metabolism or cell signalling. In this context, it is now becoming clear why antioxidants or hyperactivation of antioxidant pathways with electrophilic therapeutics can be deleterious. Furthermore, it suggests that the autophagy-lysosomal pathway is particularly important in protecting the cell against redox-stress-induced proteotoxicity, since it can degrade redox-damaged proteins without causing aberrant changes to the redox network needed for metabolism or signalling. In this context, it is important to understand (i) how NRF2-mediated redox signalling, or (ii) the autophagy-mediated antioxidant/reductant pathways sense cellular damage in the context of cellular pathogenesis. Recent studies indicate that the modification of protein thiols plays an important role in the regulation of both the KEAP1-NRF2 and autophagy pathways. In the present review, we discuss evidence demonstrating that the KEAP1-NRF2 pathway and autophagy act in concert to combat the deleterious effects of proteotoxicity. These findings are discussed with a special emphasis on their impact on cardiovascular disease and neurodegeneration.