Tuberculosis is the most prevalent infectious disease and causes more deaths than any other, yet only 5%-10% of people infected by the causative agent, Mycobacterium tuberculosis, will develop the disease. Thus, natural resistance among humans is the norm. Fundamental immune responses to M. tuberculosis are being elucidated, including induction of interferon regulatory factor-1 (IRF-1). Moreover, IRF-1 has been found necessary for normal resistance to infection by mycobacteria in mice. Roles for IRF-1 in a plethora of immune system functions have been described. This review considers molecular responses to infection by M. tuberculosis that might account for induction of IRF-1 and highlights putative connections between immunomodulatory functions of IRF-1 and immune responses relevant to infection by M. tuberculosis. However, the complexity inherent in pleiotropy and redundancy limits the ability to draw firm conclusions. In many cases, it remains to be demonstrated that a particular function of IRF-1 is the basis for a known response to infection. For example, although IRF-1 is required for a Th1 cell-mediated, adaptive immune response in some circumstances, it is not known if the Th1 response to infection by M. tuberculosis requires IRF-1. Conversely, some known contributions by IRF-1 to fundamental aspects of the immune system are not yet proven relevant in the host response to infection. For example, it is not known if control of T cell subset development by IRF-1 is significant for host defense against M. tuberculosis. Functions of other IRF that overlap with or are distinct from the functions of IRF-1 also could be important for the immune response to M. tuberculosis.