This article reviews events that led to the withdrawal of the only vaccine to prevent Lyme disease licensed in the United States. The primary issues that led to the vaccine’s withdrawal appear to be a combination of vaccine safety concerns, sparked by a molecular mimicry hypothesis that suggested that the vaccine antigen, outer surface protein A, serves as an autoantigen and hence was arthritogenic; concerns raised by anti-vaccine groups regarding vaccine safety; vaccine cost; a difficult vaccination schedule and the potential need for boosters; class action lawsuits; uncertainty regarding risk of disease; and low public demand. This article reviews lessons learned from these events and proposes that future candidate Lyme disease vaccines are unlikely to be developed, tested, and used within the United States in the near future, thus leaving at-risk populations unprotected.