The mechanisms that regulate ionic balance, fluid absorption and secretion in the gastrointestinal tract are complex. Disturbance of this homeostatic state by bile acids, bacterial enterotoxins and neoplasm-derived secretagogues, for example, can lead to diarrhea. Determining the causes of chronic diarrhea in individual patients may, therefore, represent a diagnostic challenge. The gastrointestinal tract has finely tuned mechanisms to maintain ionic balance, fluid absorption and secretion. To achieve this homeostasis, various ionic transport proteins/complexes are targeted to the apical, basal or basolateral membranes of epithelial cells. Na, K and Cl ion transport proteins are regulated by endogenous activators (e.g. cAMP, PGE2, Ca), dietary-related factors (e.g. bile acids) and through post-translational modifications (e.g. phosphorylation). In certain pathophysiologic states, this homeostatic ionic/fluid exchange becomes dysfunctional as a result of failure of compensatory pro-absorptive/anti-secretory mechanisms. The excessive secretion of Na and Cl ions followed by the release of a large amount of H2O into the colonic lumen results in diarrhea, which may be acute or chronic, and can be life-threatening if not ameliorated. Diverse infectious organisms (e.g. bacteria, protozoa, viruses) utilize different mechanisms to cause intestinal disease and diarrhea. These pathophysiologic mechanisms include alterations in ion transport, disruption of tight junctions and elicitation of inflammatory responses. Studies of patients infected with certain pathogens, those with ulcerative colitis and those harboring extra-colonic or colonic neoplasms have elucidated some of these pathophysiologic mechanisms of diarrhea. Determining the etiology of chronic diarrhea in specific cases may be a diagnostic challenge for both gastroenterologists and primary care physicians.