Erythema migrans (EM) must be distinguished from other entities including streptococcal and staphylococcal cellulitis, hypersensitivity reactions to arthropod bites, plant dermatitis, tinea, and granuloma annulare. Although EM lesions may be pruritic or painful, these complaints are generally mild. Central clearing may be absent in > 50% of patients. Multiple lesions, formerly present in 50% of U.S. patients, now occur in approximately 20%. EM develops days to 1 month after a tick bite (median 7-10 days), and lesion diameter increases with duration. Most patients have associated complaints, with fatigue (54%), myalgia (44%), arthralgia (44%), headache (42%), and fever and/or chills (39%) being the most common. Respiratory and gastrointestinal complaints are infrequent. Symptoms may begin prior to the onset of, concomitant with, or after resolution of the rash. The incidence of viral-like illness due to Lyme disease without EM is unknown. Antibodies to Borrelia burgdorferi are absent in up to 50% of patients at presentation, with initial seropositivity most likely in those with EM of longer duration. The vast majority of patients will become seropositive within the first month of illness, even with treatment. Although there is evidence that B. burgdorferi can spread to the blood and central nervous system soon after onset of infection, oral therapy is highly effective in preventing objective extracutaneous complications of Lyme disease. The most appropriate choice, route of administration, and duration of therapy require further study. Because of variations in the etiologic agent between North America and Europe, comparisons of disease manifestations, treatment, and prognosis of Lyme disease must be made cautiously.