Spirochetes in the genus Borrelia are responsible for tick-borne relapsing fever and Lyme disease. Borrelia-tick interactions are highly specific as each species of Borrelia is only transmitted by one or a few closely related species of ticks. Borrelia colonize the gut or salivary glands of ticks. Several Borrelia genes required for tick colonization or transmission have been identified. Borrelia genes required for transmission are induced by a pathway controlled by the alternate sigma factors RpoN (σ54) and RpoS (σS). A protein in the gut of I. scapularis ticks that functions as a receptor for B. burgdorferi has been identified. In addition, Ixodes tick saliva has proteins that alter host hemostasis and immunity, and some of these salivary proteins directly interact with Borrelia to facilitate transmission and host infection, whereas others appear to assist Borrelia indirectly by suppressing host defense mechanisms. The exciting discoveries on Borrelia-tick interactions are also being translated into novel preventive measures such as transmission blocking vaccines.