Celiac disease is a fascinating illness, from both a clinical and research perspective. Most clinicians consider a diagnosis of celiac disease when a young patient has classic signs and symptoms of steatorrhea and severe mal-absorption. However, the typical gastrointestinal symptoms often are absent. The patient may only have subtle signs of chronic malnutrition or nonspecific gastrointestinal complaints. Celiac disease is not diagnosed commonly in the United States, at least in part because of a low clinical index of suspicion. A diagnosis of celiac disease is confirmed by a small bowel mucosa biopsy. A dramatic clinical response to a gluten-free diet verifies the diagnosis, and provides a cost-effective treatment free of significant side effects. Strict adherence to the prescribed diet usually results in a complete resolution of the symptoms and mucosal histopathologic changes. The serious, long-term complication of intestinal lymphoma also may be prevented. To the clinical investigator, celiac disease is an important model of the HLA-associated immune-mediated illnesses. A specific HLA-DQ heterodimer is found in 95% of patients, representing perhaps the strongest association of any illness with a specific class IIHLA molecule. In addition, an important environmental trigger (gluten) has been identified, providing a unique opportunity to study the interaction of gene products and environmental factors in the pathogenesis of an immune-mediated disease.