Although antibiotic treatments for tuberculosis are available, because of re-infection, drug resistance, AIDS, and economic reasons, it is unlikely that we will be able to control the global spread of tuberculosis without an effective vaccine. A number of new candidate vaccines for tuberculosis are under development and some are being evaluated for safety in normal human subjects in clinical trials. Additional vaccine candidates have been shown to be safe and effective when administered prior to infection in animal models. However, in areas of the world where tuberculosis is endemic, up to two thirds of the population are already infected with Mycobacterium tuberculosis, and it is unlikely that a new pre-exposure vaccine would have a substantial impact on disease for decades. In contrast, a vaccine that could be delivered to individuals already infected could reduce the disease burden. At this time, it is unclear whether the new TB vaccines can be safely and effectively used in populations already infected with M. tuberculosis, immunized with BCG vaccine or infected with HIV. This presents a major challenge to pre-clinical testing and clinical evaluation as well as eventual uptake of the new TB vaccines into areas of the world that are most at risk for tuberculosis.