Whipple disease is a chronic, multisystem, curable, bacterial infection that usually affects middle-aged men and has a wide range of clinical manifestations. The most common symptoms are weight loss and diarrhea, preceded in three quarters of cases by arthritis for a mean of 6 years. In most patients, periodic acid-Schiff staining of proximal small bowel biopsy specimens reveals inclusions within the macrophages, corresponding to bacterial structures. However, patients with various manifestations of the disease may have no gastrointestinal symptoms and negative jejunum biopsy results. Before the onset of gastrointestinal symptoms, a strong index of clinical suspicion is the key to diagnosis. The classic setting is long-term, unexplained, seronegative oligoarthritis or polyarthritis with a palindromic or relapsing course, although chronic destructive polyarthritis and spondyloarthropathy have been repeatedly reported. Identification of the Whipple bacterium, Tropheryma whippelii, has led to the development of polymerase chain reaction as a diagnostic tool in patients in the early stages of the disease or with atypical Whipple disease. This technique can be used to detect the bacterium in many tissues and fluids, including synovial tissue and fluid. The recent cultivation of the Whipple bacillus should lead to the development of serologic tests, further facilitating diagnosis. These recent major advances may show that the infection is more frequent than previously suspected and may expand the clinical spectrum of the disease. It may also allow earlier diagnosis, thereby preventing the development of the severe systemic and sometimes fatal forms of the disease.