Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most common vector-borne disease in the United States. The clinical presentation varies depending on the stage of the illness: early disease includes erthyma migrans, early disseminated disease includes multiple erythema migrans, meningitis, cranial nerve palsies, and carditis; late disease is primarily arthritis. The symptoms and signs of infection resolve in most patients after treatment with appropriate antimicrobials for 2 to 4 weeks. Serologic testing should be used judiciously as it often results in misdiagnosis when performed on blood from patients with a low prior probability of disease and those with only nonspecific symptoms such as fatigue or arthralgia without objective signs of infection.