The introduction of endoscopy of the upper digestive tract as a routine diagnostic procedure has increased the number of duodenal biopsy specimens. Consequently, the pathologist is often asked to evaluate them. In this review, a practical approach to the evaluation of a duodenal biopsy specimen is discussed. An overview of the handling of specimens is given and the normal histology and commonly encountered diseases are discussed. Finally, a description of commonly seen infections is provided, together with an algorithmic approach for diagnosis.