Worldwide, human brucellosis is the most common zoonotic disease and it has gained increasing interest because of the potential use of Brucella as a biological weapon. Monotherapy for brucellosis is associated with a high relapse rate and dual therapy in different combinations is more efficacious. The combination regimen of intramuscular streptomycin with an oral tetracycline resulted in fewer relapses than the doxycycline-rifampin combination in meta-analysis and prospective studies, although the use of doxycycline and rifampin is a reasonable choice in certain conditions. Longer duration and triple antimicrobial therapy appear to improve outcome and prevent relapses, especially in patients with focal disease. Recently, the use of gentamicin-loaded microparticles and the use of new antibiotics, such as tigecycline, may hold future promise. In addition, there are a few studies of the enhanced effect of immune response stimulators, such as levimasole and IFN-2, in the treatment of brucellosis. The development of an effective subcellular Brucella vaccine would be an important step forward to curtail the disease. However, currently and for the near future, only the control of animal disease is possible using vaccine strategies.