Whipple disease is a chronic, relapsing, and multisystem disease. It presents a diagnostic challenge for both clinicians and pathologists. Recent advances in isolation and culture have identified the organism responsible for the disease to be a member of the order Actinomycetes designated Tropheryma whipplei. Several immune system changes have been noted in patients with Whipple disease, but whether these are primary or secondary is as yet undetermined. Long-term antibiotic therapy is required, and relapses are common, especially with central nervous system involvement.