Diagnosis of celiac disease in adults is currently based on serologic tests in combination with histopathological assessment of small intestinal biopsy specimens. High titers of celiac-specific antibodies in immunocompetent patients with villous atrophy in a good quality biopsy sample allow us to state a confident diagnosis. The relief of symptoms and histological improvement after embarking on a gluten free diet further support the initial diagnosis. However, in some cases, these conditions are not fulfilled, which requires a critical evaluation of laboratory and histopathology results and a consideration of other potential causes for the observed pathologies. To avoid diagnostic uncertainty, both biopsy and laboratory testing should be performed on a diet containing gluten. Immune deficiency, cross reaction of antibodies and possibilities of seronegative or latent celiac disease should be considered while evaluating serology results. Uneven distribution and variable intensity of histopathological changes in the small intestine along with multiple disorders presenting a similar specimen image may lead to invalid biopsy results. Additional laboratory testing and careful examination of a patient's history may deliver important data for a differential diagnosis and a more specific biopsy evaluation. Persistence or recurrence of symptoms, despite the ongoing treatment, requires a revision of the initial diagnosis, an evaluation of the gluten free diet and a search for concurrent disorders or complications.