Tumor necrosis factor (TNF) is essential to control Mycobacterium tuberculosis (M.tb) infection and cannot be replaced by other proinflammatory cytokines. A crucial role of TNF in the control of infection has been illustrated recently by primary and reactivation of latent M.tb infection in some patients under pharmacological anti-TNF therapy for rheumatoid arthritis or Crohn’s disease. In this review, the authors discussed results of recent studies aimed at better understanding molecular, cellular and kinetic aspects of TNF-mediated regulation of host-mycobacteria interactions. In particular, recent data using either mutant mice expressing solely membrane TNF (mTNF) or specific inhibitor sparing mTNF demonstrated that mTNF is sufficient to control acute M.tb infection. This is opening the way to selective TNF neutralization that might retain the desired anti-inflammatory effect but reduce the infectious risk.