Ehrlichia are small obligately intracellular bacteria in the order Rickettsiales that are transmitted by ticks and associated with emerging life-threatening human zoonoses. Vaccines are not available for human ehrlichiosis, and therapeutic options are limited to a single antibiotic class. New technologies for exploring host-pathogen interactions have yielded recent advances in understanding the molecular interactions between Ehrlichia and the eukaryotic host cell and identified new targets for therapeutic and vaccine development, including those that target pathogen virulence mechanisms or disrupt the processes associated with ehrlichial effector proteins. Animal models have also provided insight into immunopathological mechanisms that contribute significantly to understanding severe disease manifestations, which should lead to the development of immunomodulatory approaches for treating patients nearing or experiencing severe disease states. In this review, we discuss the recent advances in our understanding of molecular and cellular pathobiology and the immunobiology of Ehrlichia infection. We identify new molecular host-pathogen interactions that can be targets of new therapeutics, and discuss prospects for treating the immunological dysregulation during acute infection that leads to life-threatening complications.