Over 600,000 vector-borne disease cases were reported in the United States (U.S.) in the past 13 years, of which more than three-quarters were tick-borne diseases. Although Lyme disease accounts for the majority of tick-borne disease cases in the U.S., tularemia cases have been increasing over the past decade, with >220 cases reported yearly. However, when comparing (causative agent of Lyme disease) and (causative agent of tularemia), the low infectious dose (<10 bacteria), high morbidity and mortality rates, and potential transmission of tularemia by multiple tick vectors have raised national concerns about future tularemia outbreaks. Despite these concerns, little is known about how is acquired by, persists in, or is transmitted by ticks. Moreover, the role of one or more tick vectors in transmitting to humans remains a major question. Finally, virtually no studies have examined how adapts to life in the tick (vs. the mammalian host), how tick endosymbionts affect infections, or whether other factors (e.g., tick immunity) impact the ability of to infect ticks. This review will assess our current understanding of each of these issues and will offer a framework for future studies, which could help us better understand tularemia and other tick-borne diseases.