Evidence from experimental models, from rare human genetic conditions, and from HIV-associated TB demonstrate that the Th1-mediated IL-12–IFN-γ axis is essential for prevention of progressive disease. Priming this response provides the major focus for the vaccine candidates currently being assessed in clinical trials. A broader view of the immune response suggests multiple alternative strategies that may influence the outcome of infection, including delivery of IFN-γ by alternative lymphocyte subsets, release of bacteria by cytolysis of poorly microbicidal cells, and activation of IFN-γ–independent pathways of mycobacterial killing. It is probable that all of these activities are subject to regulatory control mechanisms in vivo, and successful vaccination may ultimately depend on establishing or resetting multicellular immune networks rather than overactivation of a single pathway.