Celiac disease (CD) patients are intolerant to gluten, proteins in wheat, and related cereals. Virtually all patients are human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 positive and several studies have demonstrated that CD4 T cells specific for (modified) gluten peptides bound to these HLA-DQ molecules are found in patients but not in control subjects. These T cell responses are therefore thought to be responsible for disease development. Many immunogenic gluten peptides which may relate to the disease-inducing properties of gluten have now been identified. In addition, gluten can stimulate IL-15 production that ultimately leads to NKG2D-mediated epithelial cell killing. However, CD develops in only a minority of HLA-DQ2 and HLA-DQ8 individuals. This may be attributed to the default setting of the intestinal immune system: induction and maintenance of tolerance to dietary components and commensal flora. Although at present it is unknown why tolerance in CD is not established or broken, both environmental and genetic factors have been implicated. There is strong evidence for the existence of genes or gene variants on chromosomes 5, 6, and 19 that predispose to CD. In addition, type I interferons have been implicated in development of several autoimmune disorders, including CD. Thus, viral infection and/or tissue damage in the intestine may cause inflammation and induce protective Th1-mediated immunity leading to loss of tolerance for gluten. Once tolerance is broken, a broad gluten-reactive T cell repertoire may develop through determinant spreading. This may be a critical step toward full-blown disease.