A number of gastrointestinal and hepatobiliary disorders are thought to have an immunologic basis; however, the level of understanding of immunopathogenesis varies widely in these disparate conditions. For some, such as celiac disease, both important genetic and environmental determinants have been identified as well as a specific treatment. For others, such as pernicious anemia and inflammatory bowel disease, animal models have provided important research advances. Two conditions, inflammatory bowel disease and sclerosing cholangitis, are strongly associated. Characteristic immunologic features of these diseases are critical for diagnosis. Although the majority of conditions are currently treated with nonselective anti-inflammatory and immunosuppressive agents, recent research has introduced novel biological agents, exemplified by the successful use of infliximab for Crohn's disease. (J Allergy Clin Immunol 2003;111:S645-58.)