Whipple's disease was described in 1907 and was designated "intestinal lipodystrophy," despite the detection of bacteria in 1 specimen. This finding was later substantiated by the success of antibiotic therapy, which resulted in dramatic clinical responses, and by use of electron microscopy, which detected monomorphic bacilli in affected tissues. Many attempts at culture failed, and these bacteria were characterized as actinomycetes for the first time by means of broad-range 16S rDNA amplification and molecular phylogenetic methods. The name "Tropheryma whippelii" was proposed for this bacterium. Whipple's disease is a systemic disease that affects many organ systems, producing protean manifestations. This article summarizes recent developments with regard to this topic as well as unanswered questions regarding the pathogenesis and acquisition of infection, the biology and ecology of the organism, the clinical spectrum of disease, diagnosis of the disease, and therapy.