The endoplasmic reticulum (ER) plays a crucial role in protein synthesis, folding, and calcium homeostasis. Disruptions in these functions, such as alterations in calcium levels and the accumulation of misfolded proteins, lead to ER stress, which can ultimately trigger apoptosis. Prolonged ER stress is linked to several neurodegenerative disorders characterized by the accumulation of misfolded proteins. Apoptosis involves the activation of intracellular signaling pathways, including the caspase family of cysteine proteases, leading to cell death. Recent studies have identified the ER as a third subcellular compartment involved in apoptotic execution, alongside the mitochondria and death receptors. The ER contains proapoptotic and antiapoptotic molecules, such as caspase-12, p28Bap31, GADD153, GRP78, calreticulin, PDI, ORP-150, and Bcl-2 family members. These molecules act as sensors, modulators, or effectors in the ER stress-induced cell death pathway. The ER stress-induced cell death modulators include Bcl-2 family proteins, CHOP/Gadd153, VCP, and ALG-2, while the effectors include caspase-12 and BAP31. Understanding the molecular components and pathways involved in ER stress-induced cell death is essential for developing therapeutic strategies for degenerative disorders characterized by misfolded proteins.The endoplasmic reticulum (ER) plays a crucial role in protein synthesis, folding, and calcium homeostasis. Disruptions in these functions, such as alterations in calcium levels and the accumulation of misfolded proteins, lead to ER stress, which can ultimately trigger apoptosis. Prolonged ER stress is linked to several neurodegenerative disorders characterized by the accumulation of misfolded proteins. Apoptosis involves the activation of intracellular signaling pathways, including the caspase family of cysteine proteases, leading to cell death. Recent studies have identified the ER as a third subcellular compartment involved in apoptotic execution, alongside the mitochondria and death receptors. The ER contains proapoptotic and antiapoptotic molecules, such as caspase-12, p28Bap31, GADD153, GRP78, calreticulin, PDI, ORP-150, and Bcl-2 family members. These molecules act as sensors, modulators, or effectors in the ER stress-induced cell death pathway. The ER stress-induced cell death modulators include Bcl-2 family proteins, CHOP/Gadd153, VCP, and ALG-2, while the effectors include caspase-12 and BAP31. Understanding the molecular components and pathways involved in ER stress-induced cell death is essential for developing therapeutic strategies for degenerative disorders characterized by misfolded proteins.