Most patients with Crohn's disease undergo upper endoscopy with biopsy at least once, and for the pathologist it is of utmost importance to classify the lesions observed in biopsy specimens from the upper gastrointestinal tract. Duodenal and gastric specimens present two patterns of inflammation: a focal inflammation, with the inflammatory process restricted to a few glands, and a discontinuous inflammation, with the inflammation involving the entire or at least large parts of the specimens. In the latter, the mucosal architecture is compromised. The occurrence of epitheloid granulomas may support the diagnosis of Crohn's disease, but is not mandatory. Crohn's disease can be recognized in specimens taken from the esophagus only if granulomas or giant cells are found beneath the epithelial layer. This review discusses the most important differential diagnoses of inflammatory lesions in the upper gastrointestinal tract.