At the beginning of the last century, George Whipple reported a case of disease in a medical missionary who died after suffering from chronic arthralgias, diarrhea, weight loss, abdominal discomfort, cough, fever, hypotension, increased skin pigmentation, and severe anemia 62. The pathologic findings showed fat deposition in intestinal and mesenteric lymph nodes 62. Nowadays, Whipple's disease is being recognized with increasing frequency as the result of greater awareness of the entity, the improvement of diagnostic tools, and a possible true increase in incidence. Patients suffering from the disease often present with malabsorption and other gastrointestinal symptoms. However, articular, cardiac, and central nervous system involvement is not uncommon and may be more prominent clinically. These various manifestations reflect the systemic nature of a chronic infection associated with rod-shaped organisms. The traditional laboratory diagnosis is based on light microscopy, which shows diastase-resistant, periodic acid-Schiff (PAS)-positive, non-acid-fast granules in macrophages of intestinal biopsy specimens. The greatest concentration of these typical foamy macrophages, considered the hallmark of the disease, is in the mucosa of the small intestine and regional intestinal lymph nodes, but they have been found in a wide distribution of systemic sites, the most common being neurologic, pulmonary, or cardiovascular. In 1991, a portion of the 16S rRNA gene of the bacterium was sequenced by Wilson et al. 63, allowing the classification of the Whipple's disease bacterium within the Actinomycetes clade. One year later, these findings were confirmed and extended by Relman et al. 50. Since then, PCR has become a useful tool for the diagnosis of Whipple's disease 47. Culture of the bacterium has been an elusive goal for many generations of microbiologists 27, 55. In 2000, we reported the successful isolation and establishment of a strain of Whipple's disease bacterium obtained from the mitral valve of a patient with blood culture-negative endocarditis, the generation of antibodies against the bacterium in mice, the detection of the bacterium in the patient's mitral valve by immunochemistry with these antibodies, and the detection of specific antibodies against the bacterium in the patient's serum 48. At the beginning of this century, with the possible culture of the Whipple's disease bacterium and the new tools such as PCR, we believe that a new area has begun for the epidemiology and the diagnosis of Whipple's disease, accompanied by a more complete understanding of the infection, improved therapy, and better clinical outcomes. The past, the present, and the future of Whipple's disease are reviewed in this article.