The article reviews the roles of C/EBP homologous protein (CHOP) and growth arrest- and DNA damage-inducible gene 153 (GADD153) in endoplasmic reticulum (ER) stress-mediated apoptosis and their involvement in various diseases. ER stress occurs when protein folding is impaired, leading to unfolded or misfolded proteins that threaten cell survival. The ER has a signaling pathway to respond to ER stress, involving translational attenuation, upregulation of ER chaperone genes, ER-associated degradation (ERAD), and activation of NFκB. When ER function is severely impaired, apoptosis is induced through three pathways: transcriptional activation of CHOP, activation of the JNK pathway, and activation of caspase-12. CHOP is a 29 kDa protein with a transcriptional activation domain and a bZIP domain, which can form homodimers or heterodimers. It is ubiquitously expressed at low levels but is robustly induced by stress conditions. CHOP is regulated at both the transcriptional and post-transcriptional levels, with the latter involving mRNA stability and phosphorylation by p38 MAP kinase. CHOP plays a crucial role in ER stress-induced apoptosis, and its overexpression leads to cell cycle arrest and apoptosis. CHOP-mediated apoptosis is involved in normal cell growth and differentiation, as well as in diseases such as diabetes, brain ischemia, and neurodegenerative disorders. In diabetes, CHOP induction contributes to β-cell apoptosis and hyperglycemia. In brain ischemia, ER stress-mediated apoptosis in vulnerable neurons contributes to delayed cell death or neurodegeneration. In neurodegenerative diseases, CHOP-mediated apoptosis may be involved in the development of conditions like Alzheimer's, Parkinson's, and Huntington's diseases. The article concludes by discussing the potential therapeutic targets for CHOP-mediated apoptosis in various diseases.The article reviews the roles of C/EBP homologous protein (CHOP) and growth arrest- and DNA damage-inducible gene 153 (GADD153) in endoplasmic reticulum (ER) stress-mediated apoptosis and their involvement in various diseases. ER stress occurs when protein folding is impaired, leading to unfolded or misfolded proteins that threaten cell survival. The ER has a signaling pathway to respond to ER stress, involving translational attenuation, upregulation of ER chaperone genes, ER-associated degradation (ERAD), and activation of NFκB. When ER function is severely impaired, apoptosis is induced through three pathways: transcriptional activation of CHOP, activation of the JNK pathway, and activation of caspase-12. CHOP is a 29 kDa protein with a transcriptional activation domain and a bZIP domain, which can form homodimers or heterodimers. It is ubiquitously expressed at low levels but is robustly induced by stress conditions. CHOP is regulated at both the transcriptional and post-transcriptional levels, with the latter involving mRNA stability and phosphorylation by p38 MAP kinase. CHOP plays a crucial role in ER stress-induced apoptosis, and its overexpression leads to cell cycle arrest and apoptosis. CHOP-mediated apoptosis is involved in normal cell growth and differentiation, as well as in diseases such as diabetes, brain ischemia, and neurodegenerative disorders. In diabetes, CHOP induction contributes to β-cell apoptosis and hyperglycemia. In brain ischemia, ER stress-mediated apoptosis in vulnerable neurons contributes to delayed cell death or neurodegeneration. In neurodegenerative diseases, CHOP-mediated apoptosis may be involved in the development of conditions like Alzheimer's, Parkinson's, and Huntington's diseases. The article concludes by discussing the potential therapeutic targets for CHOP-mediated apoptosis in various diseases.