In this review we describe several genetic regulatory mechanisms adopted by the agent of Lyme disease, Borrelia burgdorferi, to sense and adapt to different host and environmental conditions either in vitro or in vivo. This regulation results in the increased or decreased synthesis of several proteins whose levels are believed to play key roles in the ability of B. burgdorferi to cycle between both arthropod and mammalian hosts. Moreover, the differential synthesis of these proteins serves to modulate the response of B. burgdorferito signals in the requisite host and may also, in some cases, function as virulence determinants of this spirochete. Elucidation of these mechanisms will help in the understanding of the pathogenicity of B. burgdorferi as well as aid in identifying proteins that are important during different stages of infection.