Mycobacterial infections cause enormous morbidity and mortality worldwide, but the critical aspects of the host response to them are still poorly understood. Over the past few years, cytokines have emerged as critical factors in mycobacterial control, with numerous mutations identified in the pathways controlling the production of, or response to, interferon gamma and its inducer, interleukin (IL)-12. These same cytokines may also have therapeutic activity against the nontuberculous mycobacteria and tuberculosis. In this article, the critical pathways and some of the relevant cytokines and studies are reviewed. This is a US government work. There are no restrictions on its use.