Erythema migrans (EM) is the most common objective manifestation of Borrelia burgdorferi infection. Systemic symptoms are usually present. Most patients do not recall a preceding tick bite. Despite a characteristic appearance, EM is not pathognomonic for Lyme disease and must be distinguished from other similar appearing skin lesions. EM is a clinical diagnosis; serologic and PCR assays are unnecessary. Leukopenia and thrombocytopenia are indicative of either an alternative diagnosis, or coinfection with another tick-borne pathogen. When EM is promptly treated with appropriate antimicrobial agents, the prognosis is excellent. Persons in endemic areas should take measures to prevent tick bites.