Tropical sprue (TS) is a clinical entity of unknown etiology characterized by an acquired chronic diarrheal illness and malabsorption that affects indigenous inhabitants and expatriates, either long-term residents or short-term visitors, in the tropical countries. The exact pathogenetic sequence of TS remains incompletely characterized. Bacterial overgrowth, disturbed gut motility, and hormonal and histopathologic abnormalities contribute to the development of TS in a susceptible host. Treatment with tetracycline and folate is effective in some patients, although relapses after treatment are common. Research in the areas of microbial factors, pathogenesis, immunogenetics, and hormonal and immune regulation, using modern diagnostic techniques, may be able to settle some of the unanswered issues and open new venues for diagnosis, prevention, and treatment of tropical sprue.