A spectrum of histological changes may be seen in coeliac disease. Interpretation of duodenal biopsies can be problematic due to inadequate specimens or difficulties in detecting the minimal histological lesion. If serology is negative but clinical suspicion is high, a duodenal biopsy should always be performed. A combination of histology, serology, morphometry and HLA typing may be helpful in equivocal cases. Small intestinal histology is the current gold-standard diagnostic test for coeliac disease. Serological tests, immunohistochemistry and HLA typing may also have a role in the diagnostic algorithm. IgA antigliadin antibodies have mainly been replaced by IgA antiendomysial antibodies and IgA antitissue transglutaminase antibodies. The high sensitivity and specificity of these new markers have been used to challenge the necessity of obtaining a duodenal biopsy to confirm the diagnosis. It is widely recognized that relying on duodenal biopsies may be problematic. In equivocal cases where the biopsy material cannot be relied on accurately, further diagnostic tests are necessary. Quantitative morphometry and immunohistochemistry may be of value in identifying intraepithelial lymphocytes and a specific subset bearing the gamma/delta receptor. HLA-DQ2 may have a role in excluding the diagnosis in equivocal cases, its main limitation being its high frequency in the normal population. Each diagnostic test, namely histology, serology or genetic typing has limitations. A combination of these diagnostic tests should be used to clarify the full breadth of the gluten sensitivity spectrum, in particular, in those cases where duodenal histology may be equivocal.