Ticks are globally distributed vectors of important pathogens of human and animal health. Since the discovery of tick resistance in 1918, the field has sought continuously for the development of effective biologic control of ticks and tick-borne pathogens. A goal of this dissertation was the refinement of a large-animal model system to study species indigenous to the United States. Further, the research described in this dissertation sought to target various aspects of the tick-pathogen-host interface. The research in chapter 2 detailed our work in high-quality sequencing of the non-tick-transmissible Anaplasma marginale Illinois strain. We identified several candidate genes and genomic elements associated with the tick-transmission of A. marginale. The research in chapter 3 sought to adapt and refine a large-animal model system to evaluate host resistance to Dermacentor andersoni ticks. Several proteins isolated from cattle with reduced tick performance were identified in calves immunized with tick salivary gland tissues. The proteins identified here are important for future experiments to determine their posited roles in reduction of tick feeding. Finally, the research in chapter 4 built on this work and suggested that immunization with native salivary gland (NSG) and native midgut (NMG) interfered with A. marginale transmission by D. andersoni. Further, NSG immunization also had the most consistent and greatest impact on D. andersoni acquisition of A. marginale. The antigens responsible for this protection remain undetermined. The results in this dissertation demonstrate that there are several facets of the tick-pathogen-host life cycle that can be targeted for mitigation of tick-borne disease.