Lyme disease is a multisystem illness caused by the spirochete Borrelia burgdorferi, and it is the most common vector-borne illness in the United States. Lyme disease is also endemic in Europe and Asia. There have been major advances in the field since the disease was first described, including the sequencing of the B. burgdorferi genome; an increase in understanding of the interactions among the spirochete, the tick, and the mammalian host; new and improved laboratory tests; and a vaccine for prevention of the disease. Still, the diagnosis of Lyme disease remains based on history and clinical findings, supplemented by careful use of laboratory tests, and requires that the physician be familiar with the disease's clinical manifestations and the shortcomings of the available diagnostic tests.