The number of reported cases of Lyme disease in the United States has increased steadily since 1982, and the increase coincides with a growth in deer populations in endemic regions. Application of careful epidemiologic principles has led to the identification of two new pathogens that produce syndromes closely related to Lyme disease. Coinfection with other pathogens such as Babesia has been shown to alter the clinical course of Lyme disease. Better understanding of the pathogenesis of Lyme disease has provided clues into the mechanisms responsible for persistent symptoms and will serve as a foundation for the design and implementation of appropriate therapic recommendations. A safe vaccine for the prevention of Lyme disease in humans has been developed, and clinical vaccine efficacy trials are close to completion.