The greatest challenge in the United States, today, is to prevent those persons who have already acquired a TB infection from developing the disease. Physicians play a critical role in meeting this challenge. The natural history of TB infection is illustrated and discussed. The least well-understood aspect of TB transmission is that of host susceptibility. Although the precise mechanisms underlying the reactivation of latent TB infection are not well-understood, there are certain clinical and epidemiological factors associated with the development of TB and these are listed along with some general strategies for TB prevention. In this regard, air-control measures such as urging patients to cover their noses and mouths when coughing, the provision of adequate ventilation in buildings, are helpful. Two approaches for providing direct protection to uninfected persons, vaccination and drug treatment or primary prophylaxis are discussed in detail. While isoniazid preventive therapy has been found to substantially reduce the risk of TB at a generally acceptable risk to the patient, for several listed reasons, this therapy is not universally applied in the US. Alternative drugs for those resistant to isoniazid, identification of candidates for preventive treatment, prescribing and management of isoniazid preventive therapy are elaborated. Consideration of the social aspects of TB and continuing the search for new, effective, preventive therapy regimens that can be delivered cheaply, safely and for relatively brief durations are recommended for future TB prevention.