Protracted diarrhea is used to describe infants with loose and frequent stools of sufficient severity to require nutritional support, most commonly parenteral nutrition. Despite similar clinical presentations, the causes of protracted diarrhea in infants are varied and diverse in management and prognosis. The following cases represent the two more common causes of protracted diarrhea in young infants in the developed world - allergic and autoimmune enteropathy. Both patients demonstrate diagnostic challenges related to clinical and/or laboratory features. These cases illustrate the important role histological assessment plays in determining the correct diagnosis, treatment course and prognosis in infants with protracted diarrhea.