Each year, many residents of and visitors to endemic regions of the western United States are exposed to the tick vectors of tick-borne relapsing fever (TBRF), Ornithodoros hermsi, Ornithodoros turicata, or Ornithodoros parkeri. This disease is remarkable because the human host is unaware of the tick bite, usually becomes very ill, may experience an exacerbation of symptoms rather than improvement shortly after beginning appropriate treatment, and, despite often high numbers of the etiologic organism in the blood, rarely dies as a result of the illness. Although relapsing fever is acquired in many parts of the world, this article focuses primarily on knowledge about TBRF in North America.