Borrelia burgdorferi, the spirochete that causes Lyme disease, exists in an enzootic cycle, alternating between a tick vector and a vertebrate host. To adapt to and survive the environmental changes associated with its enzootic cycle, including nutrient availability, B. burgdorferi uses three different systems to regulate the expression of genes: RpoN-RpoS, histidine kinase (Hk)1/response regulator 1 (Rrp1), and RelBbu. The RpoN-RpoS alternative sigma factor cascade activates genes required for transmission from the tick to the vertebrate, maintenance of the vertebrate infection, and persistence in the tick. RelBbu controls the levels of the alarmones guanosine pentaphosphate and guanosine tetraphosphate, which are necessary for surviving the nutrient-deficient conditions in the midgut of the tick following absorption of the blood meal and the subsequent molt. The Hk1/Rrp1 two-component system produces cyclic dimeric guanosine monophosphate that regulates the genes required for the transitions between the tick and vertebrate as well as protective responses to the blood meal.