Anti-tick vaccines act by damaging the parasite or by inhibiting acquisition of blood from hosts, thus decreasing the number of ticks that finish their life cycle and, consequently, the number of infesting larvae. Poor immune memory has limited usefulness of anti-tick vaccines based on “hidden”, non-salivary antigens. Tick saliva mediates parasitism by relying on proteins to attach to hosts and to counter the hemostatic, inflammatory and immune reactions of hosts; effective anti-tick vaccines must neutralize this extensive repertoire. Loads of the cattle tick, Rhipicephalus microplus, vary between breeds of cattle and are heritable; ticks feeding on genetically resistant bovines are reproductively less fit. We profiled global gene expression in salivary glands from ticks feeding on susceptible and resistant bovines; we also reacted tick salivary proteomes with sera from these hosts. Candidate antigens were chosen among sialoproteins with gene expression patterns suggestive of absent or reduced amounts in ticks feeding on resistant hosts or reactivities suggesting neutralization by resistant hosts antibodies. Antigens thus selected were tested as a four-component cocktail of recombinant proteins in calves challenged with larvae of R. microplus, and as a seven-component DNA vaccine cocktail in dogs challenged with adults of the dog tick, R. sanguineus. Compared to controls, vaccines reduced infestations by 73 and 87%, respectively; interestingly, different sets of antigens induced different effects on the tick’s life cycle. Challenges in calves boosted antibody responses to two of the four antigens, both of which presented the most predicted T cell epitopes. These results support use of a multicomponent vaccine targeting salivary proteins in order to neutralize mediators of parasitism and to recruit natural infestations as boosters of immunity. They also indicate that a cross-protective vaccine is possible against some species of ticks.