Brucellosis, in particular infections with Brucella abortus, Brucella melitensis or Brucella suis, remains a significant human health threat in many areas of the world. The persistence of pathogenic Brucella spp. in domestic livestock or free-ranging wildlife remains unresolved, despite decades of regulatory efforts worldwide. Although vaccination is probably the most economic control measure, administration of currently available vaccines alone is not sufficient for elimination of brucellosis in any host species. Complacency in brucellosis control programs usually results in failure, or at best, limited reductions in disease prevalence or incidence of human infections. New brucellosis vaccines with high efficacy and safety are needed that address the diversity in host species and can be more widely applied under field conditions. Development of safer and more efficacious vaccines alone, or combined with enhancements or increased emphasis on other regulatory program components, could have tremendous impact on reducing the worldwide prevalence of brucellosis and the associated zoonotic infections.