The major objective of this research was to gain a better understanding of the epidemiology of E. chaffeensis and E. ewingii, both emerging zoonotic pathogens vectored by the lone star tick (LST; Amblyomma americanum). The natural history of E. chaffeensis includes the LST as a vector and white-tailed deer (WTD; Odocoileus virginianus) as both a natural reservoir for E. chaffeensis and a major host of LST. Ehrlichia ewingii is also vectored by the LST and natural infections have been reported from dogs and humans, but a reservoir has not been confirmed. To delineate the geographic distribution of E. chaffeensis, a prototype surveillance system using WTD as natural sentinels was developed. To accomplish this goal, WTD from 563 counties from 18 states were tested for E. chaffeensis by serology, PCR, and culture. This sentinel system met critical criteria including diagnostic accuracy, adequacy of sample sizes and sampling intensity, key epidemiologic associations with the LST vector, and ability to detect spread of E. chaffeensis. To predict the distribution of E. chaffeensis, geostatistical (kriging) and logistic regression were conducted. Both analyses accurately predicted the distribution of E. chaffeensis and logistic regression detected climatic and land cover variables significantly associated with E. chaffeensis occurrence. The predicted E. chaffeensis distribution had good concordance with human case data. These comparisons are evidence that utilization of WTD as sentinels is an efficient alternative to human surveillance for predicting E. chaffeensis distribution and disease risk. Molecular characterization of two antigen genes (VLPT and 120-kDa) of E. chaffeensis from 102 WTD showed that multiple genetic types were present. Genetic types were not geographically clustered and co-infection of single deer and populations of deer was common. Because E. chaffeensis and E. ewingii are closely related and transmitted by the LST, deer were hypothesized to be susceptible to infection with E. ewingii. To test for E. ewingii infection, polymerase chain reaction and inoculation of fawns with whole blood from wild deer were conducted. Natural infections of WTD were detected and captive fawns were successfully infected. These data suggest that white-tailed deer may be an important reservoir for E. ewingii.