Tuberculosis remains an important bacterial disease responsible for more than one million deaths per year. The risk of overt disease is highest in the first year post infection, nevertheless, asymptomatic chronic infection (referred to as Latent Tuberculosis Infection, LTBI) may also be established. LTBI cannot be ascertained directly, it can only be inferred from a skin or blood test of immune sensitization. Nevertheless, it is often stated that one third of the world’s population has LTBI. The central tenet of Tuberculosis control has therefore been antibiotic treatment of overt disease and the selective less intensive antibiotic treatment of patients considered at risk of progression of LTBI. Much Tuberculosis research has been directed towards elucidation of the mechanisms of host susceptibility to disease. The best-characterized immune risk factor for Tuberculosis is HIV-1 co-infection. Others include anti-TNF therapies, Diabetes Mellitus, other forms of immunosuppression, and cigarette smoking. However in most clinical cases of Tuberculosis, no underlying immunological defect can be identified. Since the general assumption is that most people infected with Tuberculosis never develop disease, this suggests that most people who are exposed and infected with Mycobacterium tuberculosis harbor immunity to Tuberculosis. This encourages the hypothesis that vaccination should be possible and indeed Bacille Calmette Guérin (BCG) vaccination confers protection against disseminated disease in children. However, BCG vaccination is not associated with reduced pulmonary disease in adults, which is a significant limitation. Furthermore it has been recognized that increased resistance to Tuberculosis occurs in specific populations. These include (i) heavily exposed persons in whom tests of immune sensitization nevertheless remain persistently negative; (ii) children aged between 5 years and puberty, and (iii) persons with documented persistent positive tests of sensitization who nevertheless never manifest disease. As progress towards the elimination of Tuberculosis is insufficient under current antibiotic-based strategies, the idea to enhance immune resistance either via improved vaccination or enhanced natural immunity is important. Recent research interest has therefore increased attention on the analysis of resistance in humans. The current BCG vaccine is conventionally thought to prevent progression of established infection. However, vaccination strategies now also envisage the prevention of infection and relapse. There has been a rapid growth of interest in adjunctive host-directed immune interventions which aim to either enhance protective immunity or to regulate pathological tissue-damaging immunity. However, the idea of host-directed prevention is less widely discussed.