Celiac disease (CD) is an intestinal disorder caused by an intolerance to gluten, proteins in wheat. CD is an HLA-associated disease: virtually all patients express HLA-DQ2 or HLA-DQ8. Recent work has shown that these disease-predisposing HLA-DQ molecules bind enzymatically modified gluten peptides and these HLA-DQ peptide complexes trigger inflammatory T-cell responses in the small intestine that lead to disease. In addition, gluten induces innate immune responses that contribute to the tissue damage that is characteristic for CD. Thus, CD patients are caught between a rock and a hard place: the disease is caused by a combination of adaptive and innate immune responses that both are triggered by gluten. These findings explain the disease-inducing properties of gluten and provide valuable clues for the development of alternative treatment modalities for patients. They also may be of relevance for our understanding of other multifactorial disorders including IBD and HLA-associated autoimmune diseases.