A review by Tracy and Baumgarth illustrates the complexity of Borrelia interactions with the immune system. In a masterful, thorough discussion, the authors outline current thinking of how the family of bacteria responsible for Lyme disease and other inflammatory illness persists in animals. They do so by escaping and subverting numerous immune system pathways, most notably in the principal reservoir host, the white-footed mouse. This species of mouse does not become symptomatic, and the authors explain ways that the immune response proceeds differently in the lab mouse, which does. In addition, the bacterium alters its surface proteins during various stages of infection, which makes it a moving target, but also enhances its ability to replicate and spread within the host. Finally, the authors point out that critical components of the adaptive immune response, which allow the production of highly specific and potent antibodies and immune cells, are disabled by Borrelia infection. Further study will illuminate how to target the bacteria more effectively, and to prevent persistent infection and immune dysfunction.