All the discrete genetic defects identified to date that seem to specifically predispose to infection with NTM or BCG have occurred in the pathways involving the generation of or response to IFN-gamma (Fig. 3). This natural genetic survey therefore suggests that one of the most critical cytokines in the control of NTM and BCG is IFN-gamma. Unfortunately, this recognition does not give us a clear sense of the critical mechanism(s) involved and still leaves us at a phenomenological level of understanding. Therefore, even though IFN-gamma appears to be the most critical cytokine in the control of mycobacteria by the "experiments of nature" cited earlier, it is likely that other cytokines are involved in the more proximal events of killing of intracellular parasites and viral control. These cytokines or chemokines may perform better therapeutically than [figure: see text] does IFN-gamma if they are better able to evoke the critical antimycobacterial mechanism(s). Dissection of these pathways, identification of the most proximal factors, and exploitation of these findings for the treatment of mycobacterial and other intracellular infections is the critical charge for the future.