Lyme disease, which is caused by the spirochetal agent Borrelia burgdoferi, is the most common vector-borne illness in the United States. In 1998, the US Food and Drug Administration approved a recombinant Lyme disease vaccine that was later voluntarily withdrawn from the market by the manufacturer. Current Lyme disease prevention efforts focus on a combination of methods and approaches, including area acaricides, landscape management, host-targeted interventions, management of deer populations, and personal protective measures, such as the use of insect repellant and tick checks. Although these methods are generally safe and relatively inexpensive, the primary limitations of these methods are that their effectiveness has been difficult to demonstrate conclusively and that rates of compliance are generally poor. An effective human Lyme disease vaccine that has been adequately evaluated in the highest-risk population groups could be very beneficial in preventing Lyme disease; however, it would need to meet high standards regarding safety, efficacy, cost, and public acceptance.