The epithelial barrier theory posits that the recent rise in chronic non-communicable diseases, particularly autoimmune and allergic disorders, is linked to the disruption of the epithelial barrier by environmental agents. Global pollution and exposure to toxic substances have worsened over the past six decades due to industrialization and modernization, affecting human health. New chemicals introduced without proper health assessments have led to adverse effects on the skin and mucosal epithelial barriers. These substances, such as particulate matter, detergents, surfactants, food emulsifiers, micro- and nano-plastics, diesel exhaust, cigarette smoke, and ozone, compromise the integrity of the epithelial barrier, leading to tight-junction disruption, inflammation, cell death, oxidative stress, and metabolic regulation. The interplay of toxic substances, underlying inflammatory diseases, and medications is crucial, especially in affected tissues. This review discusses the detrimental effects of environmental barrier-damaging compounds on human health, involving cellular and molecular mechanisms. It highlights the importance of maintaining epithelial barrier integrity and the need for regulatory actions to minimize exposure to toxic substances.The epithelial barrier theory posits that the recent rise in chronic non-communicable diseases, particularly autoimmune and allergic disorders, is linked to the disruption of the epithelial barrier by environmental agents. Global pollution and exposure to toxic substances have worsened over the past six decades due to industrialization and modernization, affecting human health. New chemicals introduced without proper health assessments have led to adverse effects on the skin and mucosal epithelial barriers. These substances, such as particulate matter, detergents, surfactants, food emulsifiers, micro- and nano-plastics, diesel exhaust, cigarette smoke, and ozone, compromise the integrity of the epithelial barrier, leading to tight-junction disruption, inflammation, cell death, oxidative stress, and metabolic regulation. The interplay of toxic substances, underlying inflammatory diseases, and medications is crucial, especially in affected tissues. This review discusses the detrimental effects of environmental barrier-damaging compounds on human health, involving cellular and molecular mechanisms. It highlights the importance of maintaining epithelial barrier integrity and the need for regulatory actions to minimize exposure to toxic substances.