The article reviews the dynamic regulation of cellular proteome in the endoplasmic reticulum (ER) and the role of the unfolded protein response (UPR) in managing ER stress. ER stress, caused by the accumulation of misfolded proteins, triggers the UPR to either induce autophagy for cell survival or apoptosis for cell death. The UPR consists of three pathways—PERK, IRE1, and ATF6—which can both promote autophagy and apoptosis, depending on the level of stress. The review highlights the importance of negative and positive feedback loops within and between these pathways in fine-tuning the response to ER stress. Experimental and theoretical studies show that under physiological conditions, autophagy is induced sigmoidally, while apoptosis remains inactive. At low levels of ER stress, autophagy precedes apoptosis, but at high levels, apoptosis becomes irreversible. The article also discusses the therapeutic potential of targeting UPR components to modulate cell survival or death in various diseases, emphasizing the need for a comprehensive understanding of the regulatory network to develop effective treatments.The article reviews the dynamic regulation of cellular proteome in the endoplasmic reticulum (ER) and the role of the unfolded protein response (UPR) in managing ER stress. ER stress, caused by the accumulation of misfolded proteins, triggers the UPR to either induce autophagy for cell survival or apoptosis for cell death. The UPR consists of three pathways—PERK, IRE1, and ATF6—which can both promote autophagy and apoptosis, depending on the level of stress. The review highlights the importance of negative and positive feedback loops within and between these pathways in fine-tuning the response to ER stress. Experimental and theoretical studies show that under physiological conditions, autophagy is induced sigmoidally, while apoptosis remains inactive. At low levels of ER stress, autophagy precedes apoptosis, but at high levels, apoptosis becomes irreversible. The article also discusses the therapeutic potential of targeting UPR components to modulate cell survival or death in various diseases, emphasizing the need for a comprehensive understanding of the regulatory network to develop effective treatments.