Lyme borreliosis is due to infection with the tick-borne spirochete Borrelia burgdorferi, and is associated with persistent infection unless treated with antibiotics. The persistent nature of infection by B. burgdorferi can lead to development of chronic disease, as found in patients infected before recognition of the effectiveness of antibiotic therapy. Much speculation has surrounded the possibility that autoimmune mechanisms are involved in chronic symptoms. In most cases, involvement of autoimmunity in Lyme disease has not received experimental support. The exception is in a small group of patients with chronic arthritis whose abnormal joint symptoms persist after apparent elimination of the bacteria. In this review, the evidence supporting autoimmune mechanisms in Lyme disease will be discussed.