Clinical conditions synonymous with brucellosis have been described since the time of Hippocrates. Indeed, it has been suggested that organisms resembling brucellae have been detected in carbonized cheese from the Roman era (Capasso 2002). These observations highlight how both man and animals have lived with this disease since the days of early record keeping. Despite the numerous biotechnological improvements we now have, brucellosis remains a major worldwide zoonosis. Some countries have been successful in eradication of disease, while others, especially in the developing world still live with a huge disease burden. This review outlines some of the early significant historical milestones then brings the reader to the current challenges that face us in detection, microbial typing, taxonomy, vaccine development, understanding the host-microbial interactions and virulence mechanisms of these enigmatic bacteria.