This article reviews the microbiology, pathophysiology, epidemiology, clinical manifestations, diagnostic testing, and treatment of Whipple’s disease, an illness caused by Tropheryma whipplei and characterized by multivariate clinical manifestations including an inflammatory arthropathy. Diagnosis is confirmed by tissue sampling with periodic acid-Schiff staining and/or polymerase chain reaction. Clinical manifestations most frequently manifest in the gastrointestinal tract, musculoskeletal system, neurologic system, heart, and eyes, but can affect any site. Successful therapy with appropriate antibiotics is potentially curable, but recurrences may occur.