Lyme disease is the most common vector-borne disease in the United States. Epidemiologic research has contributed to a better understanding of the factors involved in the geographic spread and increased incidence of the disease. Clinical features of Lyme disease, including skin, joint, cardiac, and neurologic involvement, are discussed here, along with recent studies that better characterize these clinical manifestations and more clearly define their immunopathogenesis. The diagnosis of Lyme disease is based on the clinical presentation. Laboratory testing may be helpful but has significant limitations, which we discuss in our review.