Lyme disease is the most commonly reported vector-borne disease in the United States, with the majority of cases occurring in the Northeast. It has now been three decades since the etiological agent of the disease in North America, the spirochete Borrelia burgdorferi, and its primary North American vectors, the ticks Ixodes scapularis Say and I. pacificus Cooley & Kohls, were identified. Great strides have been made in our understanding of the ecology of the vectors and disease agent, and this knowledge has been used to design a wide range of prevention and control strategies. However, despite these advances, the number of Lyme disease cases have steadily increased. In this article, we assess potential reasons for the continued lack of success in prevention and control of Lyme disease in the northeastern United States, and identify conceptual areas where additional knowledge could be used to improve Lyme disease prevention and control strategies. Some of these areas include: 1) identifying critical host infestation rates required to maintain enzootic transmission of B. burgdorferi, 2) understanding how habitat diversity and forest fragmentation impacts acarological risk of exposure to B. burgdorferi and the ability of interventions to reduce risk, 3) quantifying the epidemiological outcomes of interventions focusing on ticks or vertebrate reservoirs, and 4) refining knowledge of how human behavior influences Lyme disease risk and identifying barriers to the adoption of personal protective measures and environmental tick management.