Intestinal biopsies constitute an ever-increasing portion of the pathologist's workload, accounting for nearly two-thirds of specimens accessioned yearly by the pathology department at The Children's Hospital of Philadelphia. The widespread use of endoscopy and gastrointestinal biopsies in current clinical practice presents the pathologist with a diversity of intestinal mucosal appearances corresponding to disease states of variable clinical severity, requiring close collaboration between clinician and pathologist for optimal interpretation. Many of the entities resulting in severe diarrhea of infancy have been recognized only in the last several decades, and although rare, the study of these disorders, especially when combined with the powerful methods of present-day genetics and molecular biology, has afforded important insights into enterocyte development and function, and intestinal immunity and tolerance. Other conditions once considered infrequent, such as celiac disease, have now been recognized to be much more common and can present with a wide range of pathologic features.