The technique of gene targeting (knockout) has swept through biomedical research. Cytokine research has been revolutionized by knockouts and since then this technique has been widely utilized in various research fields including immunological, inflammation research and human disease model. This paper focuses on knockout mice in tuberculosis research among many infectious diseases. We have generated several knockout mice for inflammation research. After we infected various kinds of knockout mice suffering from Mycobacterium tuberculosis by aerosol infection, we investigated the roles of cytokines and transcription factors that regulate cytokines. We used knockout mice lacking IFN-γ, TNF-α, IL-18, IL-1 α / β, IL-4, IL-1 type 1 receptor, NF-IL6, TLR-2, TLR-6, interferon regulatory factor-1 (IRF-1), NK-κB p50, signal transducer and activator of transcription (STAT)1, STAT4, NKT cells and MyD88 genes in our experimental tuberculosis research. M. tuberculosis-infected knockout mice displayed various histopathologies depending on the degree of importance of the molecules in defense against tuberculosis. IFN-γ, TNF-α, IRF-1, NF-IL6, NF-κB p50, STAT1 and STAT4 knockout mice succumbed to M. tuberculosis infection over time. The results indicate that these molecules play major roles for defense against tuberculosis. These knockout mice are essential for investigating their roles in experimental tuberculosis.