The clinical spectrum of celiac disease continues to evolve. What was once thought to be a rare disorder affecting young children is now recognized to be very common with a range of symptoms from asymptomatic disease to severely affected persons. Screening for celiac disease has become relatively easily with reliable antibodies against self-antigens (TG) and modified environmental antigens (DGP). Diagnosis is confirmed by small intestinal biopsy with characteristic changes graded by the Marsh score. Elimination of gluten from the diet has been the standard of care for the last half century. Patients often have difficulty adhering to a gluten-free diet, and the failure of symptoms, antibody levels, or pathologic changes to improve after initiating the diet may be largely due to this difficulty. The genetic risk for celiac disease is largely related to HLA genotypes, with over 90% of subjects with celiac disease positive for DQ2 and the remainder positive for DQ8. The HLA association with celiac disease is largely accountable for its link to other autoimmune diseases, including type 1 diabetes and autoimmune thyroid disease, and the majority of risk for celiac disease in these populations is related to HLA genotype. Celiac disease also carries an increased risk for type 1 diabetes and autoimmune thyroid disease. Genetic syndromes such as Turner and Down syndromes are associated with an increased risk for celiac disease. Practitioners can identify groups of subjects at high risk for celiac disease and perform screening with celiac disease-related antibodies.