Lyme disease, the multisystem infectious disease caused by the tickborne spirochete Borrelia burgdorferi, frequently affects the peripheral and central nervous systems. The earliest indication of Lyme disease infection is usually erythema migrans. This large, typically macular erythema, often with a target-like pattern of concentric pale and red circles, gradually enlarges day by day, potentially reaching many centimeters in diameter. In a significant proportion of infected individuals, an acute disseminated phase leads to seeding elsewhere in the body. Up to 5% of patients develop cardiac involvement. In about 10% to 15% of patients, the nervous system becomes symptomatically involved. Current serologic diagnostic tools are quite useful, and standard treatment regimens are highly effective. Oral antimicrobials have been shown to be effective in European neuroborreliosis and presumably are equally potent in North American patients. Long-term antibiotic treatment does not provide any additional lasting improvement, but it is frequently associated with significant morbidity.