The intestinal epithelial barrier plays a crucial role in regulating interactions between luminal contents, the underlying immune system, and the rest of the body, while facilitating nutrient and waste transport. Compromised barrier function is associated with various diseases, but current clinical data are correlative, making it difficult to establish a causal link. Experimental animal models suggest that compromised epithelial integrity may contribute to specific gastrointestinal diseases, but no FDA-approved therapies targeting the epithelial barrier are currently available. Understanding disease pathogenesis and barrier regulation mechanisms is essential for developing effective therapies. The epithelial barrier function depends on a contiguous layer of cells and intercellular junctions, including tight junctions, adherens junctions, and desmosomes. These junctions regulate paracellular transport and maintain barrier integrity. Key proteins involved in tight junction regulation include claudins, occludin, and ZO-1, which interact with actin and myosin networks. Pathophysiological stimuli, such as interleukin (IL)-13 and tumor necrosis factor-α (TNF), can dysregulate tight junction function, leading to increased permeability and disease progression. Mouse models have provided valuable insights into the role of the epithelial barrier in inflammatory diseases like colitis and celiac disease. Targeting the epithelial barrier for therapy is promising, but challenges remain, including the need for more specific and effective drugs. Current best practices for treating epithelial barrier loss involve addressing the underlying disease, as increased permeability is often a consequence rather than a cause. Further research is needed to define the mechanisms of epithelial homeostasis and disease pathogenesis before therapeutic targeting of the epithelial barrier can be fully realized.The intestinal epithelial barrier plays a crucial role in regulating interactions between luminal contents, the underlying immune system, and the rest of the body, while facilitating nutrient and waste transport. Compromised barrier function is associated with various diseases, but current clinical data are correlative, making it difficult to establish a causal link. Experimental animal models suggest that compromised epithelial integrity may contribute to specific gastrointestinal diseases, but no FDA-approved therapies targeting the epithelial barrier are currently available. Understanding disease pathogenesis and barrier regulation mechanisms is essential for developing effective therapies. The epithelial barrier function depends on a contiguous layer of cells and intercellular junctions, including tight junctions, adherens junctions, and desmosomes. These junctions regulate paracellular transport and maintain barrier integrity. Key proteins involved in tight junction regulation include claudins, occludin, and ZO-1, which interact with actin and myosin networks. Pathophysiological stimuli, such as interleukin (IL)-13 and tumor necrosis factor-α (TNF), can dysregulate tight junction function, leading to increased permeability and disease progression. Mouse models have provided valuable insights into the role of the epithelial barrier in inflammatory diseases like colitis and celiac disease. Targeting the epithelial barrier for therapy is promising, but challenges remain, including the need for more specific and effective drugs. Current best practices for treating epithelial barrier loss involve addressing the underlying disease, as increased permeability is often a consequence rather than a cause. Further research is needed to define the mechanisms of epithelial homeostasis and disease pathogenesis before therapeutic targeting of the epithelial barrier can be fully realized.