Activating transcription factor 6 (ATF6) is a crucial signaling molecule in the unfolded protein response (UPR) to endoplasmic reticulum stress (ERS). ATF6 plays a significant role in the pathogenesis of various diseases, including congenital retinal disease, liver fibrosis, and ankylosing spondylitis. After ERS, ATF6 separates from binding immunoglobulin protein (GRP78/BiP) in the endoplasmic reticulum and is transported to the Golgi apparatus, where it is hydrolyzed by site 1 and site 2 proteases into fragments that localize to the nucleus and regulate the transcription and expression of ERS-related genes. This review discusses the evidence for the pathogenic importance of ATF6 signaling in different diseases and preclinical results. ATF6 is an adaptive response factor to ERS, promoting protective and adaptive remodeling of cell physiology and recovery after acute physiological and pathological injuries. However, chronic and persistent ERS can lead to apoptosis. ATF6 is rapidly degraded upon activation, and its activity is transient. The review also highlights the role of ATF6 in inflammatory, autoimmune, and cancer diseases, such as ankylosing spondylitis, acute pancreatitis, liver fibrosis, colorectal cancer, primary Sjogren's syndrome, achromatopsia, and neurodegenerative diseases like amyotrophic lateral sclerosis and Alzheimer's disease. Targeting ATF6 molecules to treat these diseases is an area of ongoing research.Activating transcription factor 6 (ATF6) is a crucial signaling molecule in the unfolded protein response (UPR) to endoplasmic reticulum stress (ERS). ATF6 plays a significant role in the pathogenesis of various diseases, including congenital retinal disease, liver fibrosis, and ankylosing spondylitis. After ERS, ATF6 separates from binding immunoglobulin protein (GRP78/BiP) in the endoplasmic reticulum and is transported to the Golgi apparatus, where it is hydrolyzed by site 1 and site 2 proteases into fragments that localize to the nucleus and regulate the transcription and expression of ERS-related genes. This review discusses the evidence for the pathogenic importance of ATF6 signaling in different diseases and preclinical results. ATF6 is an adaptive response factor to ERS, promoting protective and adaptive remodeling of cell physiology and recovery after acute physiological and pathological injuries. However, chronic and persistent ERS can lead to apoptosis. ATF6 is rapidly degraded upon activation, and its activity is transient. The review also highlights the role of ATF6 in inflammatory, autoimmune, and cancer diseases, such as ankylosing spondylitis, acute pancreatitis, liver fibrosis, colorectal cancer, primary Sjogren's syndrome, achromatopsia, and neurodegenerative diseases like amyotrophic lateral sclerosis and Alzheimer's disease. Targeting ATF6 molecules to treat these diseases is an area of ongoing research.