This article discusses the concept of intestinal permeability and the barrier function of the gut, elaborates on tight junction structure and the dynamic nature of its composition, outlines the methods for evaluating intestinal permeability, and explores abnormal intestinal permeability in clinical disease, emphasizing its possible role in the pathogenesis of autoimmune conditions. Evidence is provided from several representative diseases for a proposed model of abnormal intestinal permeability in autoimmune disease, including a description of a molecular pathway involving a signaling protein called zonulin, which appears to regulate intestinal permeability. Finally, we speculate on mechanisms that may be responsible for increasing intestinal permeability and consider clinical implications.