Chronic diarrhea is a frequently encountered symptom in clinical practice. The etiologies for chronic diarrhea are diverse and broad with varying clinical implications. A useful method of categorizing chronic diarrhea to guide a diagnostic work-up is a pathophysiology-based framework. Chronic diarrhea may be categorized as malabsorptive, secretory, osmotic, and inflammatory or motility related. Frequently, overlap between categories may exist for any given diarrhea etiology and diagnostic testing must occur with an understanding of the differential diagnosis. Investigations to achieve a diagnosis for chronic diarrhea range from screening blood and stool tests to more directed testing such as diagnostic imaging, and endoscopic and histological evaluation. The pathophysiology-based framework proposed in this chapter will allow the clinician to select screening tests followed by targeted tests to minimize cost and complications to the patient, while providing a highly effective method to achieve an accurate diagnosis.