Since its identification, information concerning Tropheryma whipplei, the causative agent of Whipple's disease (WD), has increased. Although T. whipplei is commonly infecting humans, WD is rare. The bacterium is most likely transmitted among humans via the oro-oral and the feco-oral routes. Infections result in chronic conditions such as asymptomatic carriage, disseminated Whipple's disease, which is usually preceded by arthralgias, and localized infections, such as endocarditis or encephalitis. T. whipplei is associated with acute infections including gastroenteritis, pneumonia, and/or bacteremia. Screening, based on the combined analyses of saliva and stool specimens using specific quantitative PCR, is useful if WD is suspected. Doxycycline and hydroxychloroquine for 12 months is the best treatment for WD; it should be followed by life-long treatment with doxycycline, as potentially fatal relapses can occur. T. whipplei seems to be an opportunistic bacterium that causes chronic infections in susceptible patients with as yet unknown predisposing factors. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.