Technical Abstract: Live attenuated brucellosis vaccines have been available for protecting domestic livestock against B. melitensis or B. abortus for more than 60 years. Current vaccines are effective in preventing abortion and transmission of brucellosis, but poor at preventing infection or seroconversion. In addition, they can induce abortions in pregnant animals and are infectious to humans. It can be argued that current vaccines were developed empirically in that the immunologic mechanism(s) of action were not determined. Current knowledge suggests that both the innate and adaptive immune responses contribute to immunity against intracellular pathogens and that binding of pathogen structures onto pattern recognition receptors (PMRs) is critical to development of adaptive immunity. The phagosome appears to be critical for presentation of antigens to T cell subtypes that provide protective immunity to intracellular pathogens. The observations that killed bacteria or subunit vaccines do not appear to fully stimulate PMRs or mimic Brucella trafficking through phagosomes, may explain their inability to induce immunity that equals protection provided by live attenuated vaccines. Brucella appears to have multiple mechanisms that subvert innate and adaptive immunity and prevent or minimize immunologic responses. New technologies, such as DNA vaccines and nanoparticles, may be capable of delivering Brucella antigens in a manner that induces protective immunity in domestic livestock or wildlife reservoirs of brucellosis. Because of the reemergence of brucellosis worldwide with increasing incidence of human infection, there is currently a great need for improved brucellosis vaccines. The greatest need is for new or improved vaccines against B. melitensis or B. suis.