Lyme disease spirochetes, Borrelia burgdorferi sensu lato, have adapted very well to both surviving and persisting in the mammalian host despite a strong host antibody response. It appears that both temporal and spatial regulation of outer surface proteins have contributed to this persistence. The spirochetes are able to bind fH and FHL-1 to their surface, resulting in decreased complement activation. In addition, the organisms have taken advantage of components of tick saliva to aid in their initial immune evasion and dissemination. Studies leading to these conclusions are reviewed here.