Protein-losing enteropathy (PLE) is a rare syndrome of gastrointestinal protein loss that may complicate a variety of diseases. The primary causes can be divided into erosive gastrointestinal disorders, nonerosive gastrointestinal disorders, and disorders involving increased central venous pressure or mesenteric lymphatic obstruction. The diagnosis of PLE should be considered in patients with hypoproteinemia after other causes, such as malnutrition, proteinuria, and impaired protein synthesis due to cirrhosis, have been excluded. The diagnosis of PLE is most commonly based on the determination of fecal alpha-1 antitrypsin clearance. Treatment of PLE targets the underlying disease but also includes dietary modification, supportive care, and maintenance of nutritional status. In this article, cases illustrating a variety of clinical presentations and etiologies of PLE are presented, and its diagnostic approach and treatment are reviewed.