Endoscopic biopsies of the mucosa of the large and small intestines can present the pathologist with daunting challenges, in particular because of the breadth of the differential diagnosis, which may include neoplastic, ischemic, iatrogenic (notably medication related), autoimmune, idiopathic, and infectious entities. The purpose of the present study was to develop a logical and systematic approach to the diagnosis of mucosal infections by identifying several morphologic compartments in the intestinal mucosa, and establishing a differential diagnosis for the organisms that are associated with each compartment. The organisms involved may be identified by their appearances in histologic sections, or by the nature of the host reaction to their presence. The process of systematically examining each compartment of the mucosa and scanning for evidence of infection is performed subconsciously by many pathologists, and we have found this approach to be particularly appreciated by pathologists in training.