Whipple's disease is a chronic systemic infectious disease caused by Tropheryma whippelii that typically involves the small intestine and causes malabsorption. Extraintestinal manifestations such as arthritis and fever are common and often exist prior to the onset of gastrointestinal symptoms. Involvement of the central nervous system can occur and lead to permanent sequelae. Weight loss, hyperpigmentation, and lymphadenopathy are frequent findings. The definitive diagnosis is made by biopsy of the small intestine mucosa which reveals infiltration of the lamina propria of the small intestine with periodic acid-Schiff positive macrophages. Treatment with trimethoprim combined with sulfamethoxazole for 1 year usually results in clinical remission and an excellent prognosis. Recent advances using molecular techniques to identify the uncultured bacillus of Whipple's disease should lead to a better understanding of the pathophysiology and allow for the development of a sensitive noninvasive diagnostic test.