Tick-borne spirochetes in the genus Borrelia cause significant human morbidity and mortality throughout much of the world. The discovery in late 1981 that Lyme disease is also caused by a tick-transmitted species of Borrelia built upon the seminal observations dating back to Dr. David Livingstone during his explorations across southern Africa in the mid 1850s. The early history of borrelia research will be reviewed, followed by a description of two spirochetes and the ticks associated with Lyme disease and relapsing fever in North America. The molecular adaptations used by these bacteria to ensure transmission by their blood-feeding, arthropod vectors are largely unknown. Studies performed in our laboratory with the Lyme disease spirochete, Borrelia burgdorferi, and the relapsing fever spirochete, Borrelia hermsii, in their respective tick vectors are beginning to shed light on the possible role of specific outer surface proteins differentially produced by these bacteria as they alternate between ticks and mammals. Genomic comparisons of these two spirochetes will also be discussed in relation to fundamental differences in their pathogenicity in mammals for acquisition by slow- versus fast-feeding ticks.