This chapter focuses on Lyme disease, a systemic illness caused by the spirochete Borrelia burgdorferi, considered the most common tick-borne disease in the United States. Since the original discovery of Lyme arthritis in the mid 1970s, the clinical spectrum of Lyme disease has been expanded to include a wide variety of organ systems, primarily the skin, joints, nervous system, and heart. The chapter emphasizes Lyme disease’s protean symptoms, the uncertainty of diagnosis due to lack of definitive testing methods, and the public fear of late sequelae of disease, all of which often lead to overdiagnosis and overtreatment. The chapter promotes a better understanding of the natural history, epidemiology, and pathogenesis of Lyme disease, which can help in the often confusing and difficult decisions related to diagnosis and treatment.