More than a century after the discovery of tuberculosis, mycobacterial infections are resurgent. The recent identification of mutations affecting the control of mycobacteria offer critical insights into the pathways necessary for the control of intracellular pathogens and bring us several steps closer to understanding the basic mechanisms involved. Therapy, which until recently seemed simple and straightforward, is now complicated by the emergence of drug-resistant organisms and immunocompromised hosts. Despite these problems, multidrug therapy remains the mainstay of successful treatment. Adjuvant cytokines such as IL-2, IFN-gamma, IL-12, and GM-CSF hold great promise for shortening the duration of treatment and overcoming drug resistance. Control of cytokine production by agents such as thalidomide opens the door to selective control of deleterious parts of the inflammatory response while effective drug treatment is instituted. Modulation of the host response in the fight against mycobacteria will be the focus of the next decades, and it promises to be at the forefront of immunotherapeutics.