Celiac disease (CD) is strongly associated with HLA-DQ2 and HLA-DQ8, HLA-class II molecules that present antigen-derived peptides to CD4 T cells. Indeed, proinflammatory CD4 T cells specific for gluten-derived peptides bound to HLA-DQ2 or HLA-DQ8 are present in the lamina propria of patients, and not found in nonceliac controls. While gluten peptides bind poorly to HLA-DQ2/8, modification by tissue tranglutaminase converts the neutral amino acid glutamine into glutamic acid, introducing a negative charge that allows high affinity binding. Thus, the association between CD and HLA-DQ2/8 is well understood. What is less clear is why only a small minority of HLA-DQ2/8 positive individuals develops CD, why disease can develop at any stage in life and present with highly variable symptoms. I discuss this in the framework of the multiple hit model: next to genetic predisposition, multiple other factors—some extrinsic, some intrinsic—can favour or protect from disease development.