Whipple's disease is a chronic systemic bacterial infection that predominantly affects middle-aged men. Antimicrobial therapy is curative. The causative agent has been identified as Tropheryma whippelii. A PCR-based diagnostic test is now available and is particularly useful in patients with early-stage or atypical disease. The test can detect bacterial nucleic acids in tissues and body fluids, including joint fluid. Studies using this test found no evidence that T. whippelii may be a common cause of unexplained seronegative oligoarthritis or polyarthritis. Further work is needed to identify the patient subsets most likely to benefit from T. whippelii PCR testing in joint specimens. Isolation of the organism has been achieved recently. This will probably allow development of a serological test, which may facilitate the diagnosis. Weight loss and diarrhea are the most common symptoms of Whipple's disease. Joint manifestations antedate the intestinal complaints in three-fourths of patients, the mean interval being 6 years. In most patients, duodenal and jejunal biopsy specimens contain macrophages filled with PAS-stained granules corresponding to bacteria. Nevertheless, some patients have no intestinal symptoms, and a few have normal intestinal histological findings. Before the onset of intestinal symptoms, several clinical patterns should suggest Whipple's disease. Unexplained, chronic, seronegative oligoarthritis or polyarthritis affecting the large limb joints is the most common presentation. A characteristic feature is the intermittent occurrence of the joint manifestations, at least early in the disease. Other patterns are destructive polyarthritis and spondyloarthropathy. The major advances made recently in techniques for detecting and isolating the causative agent may show that Whipple's disease is more common and has a broader clinical spectrum than was previously thought. Another hope is that the diagnosis will be made earlier, before the development of potentially fatal systemic complications.