In spite of modern diagnostic possibilities, the diagnosis of celiac disease is still challenging for the physician. This is due to the great variability of the clinical presentation. Nowadays, the classical symptoms like diarrhea, weight loss and abdominal pain are seen less often. It has become evident that celiac disease is not merely a disease of the intestine but of the entire organism. Furthermore, extraintestinal manifestations can present without any gastrointestinal symptoms. It is likely that in many cases the immune system and not nutrient deficiencies play a major role. In addition, the diagnostic tests are not always unequivocal. There is a great variability of the small intestinal changes which are sometimes in contradiction to the antibody results. Since celiac disease implies a lifelong gluten-free diet, a firm diagnosis should be obtained. Thus, one should not rely on a single test but should rather consider serology, histology and clinical response altogether.