Tuberculosis (TB) remains a leading cause of infectious disease mortality worldwide, accounting for nearly 2 million deaths annually. Despite the availability of effective anti-TB therapy, the world's case burden of TB continues to climb, in part owing to the concurrent acquired immune deficiency syndrome pandemic. The widespread use of the current TB vaccine, the bacille Calmette-Guérin strain of M. bovis (BCG), has failed to curtail the TB epidemic and therefore strategies for the eradication of TB have centered on aggressive case-finding and managed treatment, such as directly observed treatment short course (DOTS). Although DOTS continues to have a significant impact, the ability of DOTS to eradicate TB is limited. Therefore, TB eradication will require the development of an improved vaccine, which, in turn, will require application of state-of-the-art vaccine technology and of our knowledge of TB immunology and TB genomics to this problem. In this article, knowledge about the requisite components of protective immunity, modern vaccine strategies, and elements of clinical trials required to evaluate vaccine efficacy, as well as the status of current TB vaccine candidates, are reviewed.