Musculoskeletal involvement, particularly arthritis, is a common feature of Lyme disease. Early in the illness, patients may experience migratory musculoskeletal pain in joints, bursae, tendons, muscle, or bone in one or a few locations at a time, frequently lasting only hours or days in a given location. Weeks to months later, after the development of a marked cellular and humoral immune response to the spirochete, untreated patients often have intermittent or chronic monoarticular or oligoarticular arthritis-primarily in large joints, especially the knee-during a period of several years. The diagnosis of Lyme arthritis is usually based on the presence of this characteristic clinical picture, exposure in an endemic area, and an elevated immunoglobulin G antibody response to Borrelia burgdorferi. In addition, spirochetal DNA can often be detected in joint fluid by polymerase chain reaction. Lyme arthritis can usually be treated successfully with 1-month courses of oral doxycycline or amoxicillin or with 2- to 4-week courses of intravenous ceftriaxone. However, patients with certain genetic and immune markers may have persistent arthritis, despite treatment with oral or intravenous antibiotics. B. burgdorferi may occasionally trigger fibromyalgia, a chronic pain syndrome with diffuse joint and muscle symptoms. This syndrome does not appear to respond to antibiotic therapy.