Lyme disease (Lyme borreliosis) is the most common vector-borne disease of humans in the U.S. and Europe and also involves a number of domestic animals, such as dogs and horses. The Centers for Disease Control has classified Lyme disease as an “emerging epidemic.” It recently estimated the number of human cases to exceed 300,000/year in the US alone. The disease is caused by a spirochetal bacterium, Borrelia burgdorferi, is vectored by the hard tick, Ixodes spp., and is endemic to many parts of the U.S., including regions of California. Diagnosis and treatment of this complex disease pose many challenges, requiring in-depth understanding of the host-agent interaction, including mechanisms of disease induction, disease resolution, persistence, immune response, and therapeutic approaches. The Barthold laboratory has developed and refined a laboratory mouse model, which allows investigation of disease pathogenesis and immune-mediated disease resolution, mechanisms of persistence, and tolerance of Borrelia to antibiotic treatment. The Baumgarth laboratory is using the mouse model to investigate the host immune response to infection. The current focus of that work is centered on B cell-mediated immunity and their recent findings that many hallmarks of long-lived humoral immunity, such as affinity-maturation and memory B cell development following B. burgdorferi infection are severely delayed or absent. The ultimate goal of this work is to improve diagnostics and to provide mechanistic information that can be used to develop effective strategies to clear the infection by improving on the host’s own immune system.