It is firmly established that interferon-gamma (IFN-gamma) plays a mandatory role in acquired protective immunity to pathogenic mycobacteria and other intracellular pathogens. Therefore, it seems conceivable that application of recombinant IFN-gamma could be exploited for the treatment of tuberculosis. However, the results of experimental studies and clinical trials, conducted mostly in patients with multidrug resistant (MDR) disease, have thus far been only moderately encouraging. Further studies are now needed to determine if a greater clinical benefit from IFN-gamma could be obtained for the prophylactic treatment of latent tuberculosis infection and for shortening of the protracted standard chemotherapy regimen. Thus, aerosolized IFN-gamma treatment could be particularly beneficial to AIDS patients at high risk of developing mycobacterial infections, that is, those with significantly declined CD4(+) T cell counts. This review describes the current state of research on IFN-gamma interventions in tuberculosis and related infections and highlights some of the future opportunities.