Tumor necrosis factor alpha (TNF-α) is a critical immune mediator in protection against and pathology of tuberculosis (TB). TNF-α had been found to be associated with TB when it was originally identified as cachexin and until today TB research continues to unveil novel roles of this cytokine of highest relevance for the disease process and for novel intervention strategies. The essentiality of TNF-α for containment of active TB is reflected by redundancy of cellular sources of this cytokine, by complexity of mechanisms regulating TNF-α abundance and by substantial polyfunctionality of this mediator. The propensity of TNF-α to modulate granuloma biogenesis and integrity in TB represents the quintessential process in infection outcome. The TNF-α signaling pathway has proved amenable for therapy of autoimmune and other chronic inflammatory noninfectious diseases. Whether or not, and to which extent, host-directed therapies based on this cytokine will reach the patient as adjunct therapy against TB remains to be seen.