Lyme disease (Lyme borreliosis) is the most common vector-borne disease of humans in the U.S. and also involves a number of domestic animals. The Centers for Disease Control has recently classified Lyme disease as an “emerging epidemic.” 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 collaborates with the Barthold laboratory in investigating the host immune response to infection, in an effort to understand mechanisms of host immunity and bacterial persistence.