The clinical features of Lyme disease have been well documented since its description as a distinct clinical entity in 1975. A better understanding of the diversity of Borrelia strains and species that cause the disease as well as new insights into the immunology and pathogenesis of Lyme disease help explain some of the observed variations in clinical manifestations. The diagnosis of Lyme disease may be straightforward when patients in endemic areas present with typical clinical features; however, the diagnosis should be in doubt when the clinical picture is nonspecific or atypical, or a feasible exposure history cannot be obtained. Laboratory diagnosis is primarily based on serologic techniques, but interpretation of test results can be fraught with uncertainty. Treatment with appropriate antibiotics is successful in the majority of cases of Lyme disease. However, some patients may not respond, and in these cases multiple repeated courses are usually ineffective and unwarranted. More data are needed to determine the appropriate treatment of Lyme disease during pregnancy, and the appropriate management of ixodes tick bites. A suitable arthropod vector and a competent animal reservoir host are essential for perpetuating Lyme disease in a geographic location. The intricate ecologic forces at work are well understood in certain endemic areas but are poorly defined elsewhere, particularly where the disease is sporadic or its existence is in question. Prevention of Lyme disease is best achieved through education regarding avoidance of the tick vector. A vaccine using a recombinant form of the OspA protein of B. burgdorferi has been successful in animal models. Whether an effective human vaccine can be developed remains unknown.