Tuberculosis is responsible for 1.5 million deaths per year, despite available drugs and a vaccine given to infants in most countries. The vaccine lacks effectiveness against pulmonary tuberculosis, and we still do not understand the immune responses necessary for full protection against Mycobacterium tuberculosis infection or disease. In our lab, we have developed several non-human primate (macaque) models of M. tuberculosis infection, as well as different models of protection against infection or disease. These include protection at the granuloma level, vaccine induced protection using intravenous administration of the live vaccine BCG, and concomitant immunity, which is protection against reinfection. Using various tools and technologies, we are investigating the cell types and functions underlying protection in these model systems. Each of these protection scenarios may have unique and common factors that promote protection, supporting our hypothesis that there are various paths to control and failure to control infection and disease.