Control of Mycobacterium tuberculosis (Mtb) infection is a result of a successful immune response that requires priming and activation of antigen-specific CD4+ and CD8+ T lymphocytes, recruitment of cells to the infection site (typically the lung), and production of cytokines, some of whose role is to activate macrophages. This leads to inhibition or killing of some but not all bacilli. Immunological structures (granulomas) form in the lung in response to persistent antigen and cytokine and chemokine signals. In 95% of infected hosts, M. tuberculosis (Mtb) persists without causing symptoms or disease. Latent infection can subsequently reactivate to cause active TB. Experimental evidence has revealed that tumor necrosis factor (TNF) plays a major role in host defense against Mtb in both the active and chronic phases of infection [1–4]. TNF action increases the phagocytosis by macrophages and enhances mycobacterial killing in concert with IFN-c [3, 5]. TNF is crucial in recruitment of inflammatory cells, stimulating chemokine production [6] and inducing adhesion molecules on vascular endothelium [7]. Table S1 summarizes data regarding TNF in Mtb murine models. TNF is a crucial component of both antibacterial protection and the inflammatory immune response. TNF-deficient mice exhibit disorganized granulomas, altered tissue pathology, high bacterial loads, and reduced survival [2, 3]. TNF also possesses tissue-injuring properties that manifest in clinical settings including inflammation, auto-immune diseases, and transplant rejections [8, 9]. In TB patients, peripheral increases in TNF have been implicated in clinical worsening [10]. In the absence of TNF signaling, disruption of granulomatous formation as well as dissolution of granulo-