Tuberculosis is a leading cause of death from infectious diseases world-wide, and multidrug-resistant (MDR) tuberculosis continues to spread in many parts of the world. MDR tuberculosis is a potential bioterrorist threat, as therapy is prolonged with potentially toxic agents, and the cure rate is much lower than that for treatment of drug-susceptible tuberculosis. Development of methods to enhance innate and adaptive defenses against M. tuberculosis are an attractive means to provide protection against both MDR and drug-susceptible tuberculosis. Before such strategies can be developed, an improved understanding must be gained of the immune response to M. tuberculosis. Our laboratory is mainly focused on understanding the mechanisms by which natural killer (NK) cells lyse M. tuberculosis-infected cells, determining the molecular mechanisms involved in the induction of regulatory T cells (Tregs), and characterizing the mechanisms by which NK cells affect expansion of Tregs in M. tuberculosis infection. As several studies demonstrated defective immune responses in tuberculosis patients, our studies will pinpoint the nature of this defective immune response and permit development of methods to reverse this defect. In the long run, these findings will permit development of novel methods to stimulate immunity against tuberculosis, a strategy that will contribute to development of an effective vaccine to prevent tuberculosis and novel immunotherapy to treat the disease.