The emergence and spread of drug-resistant strains of <i>Mycobacterium tuberculosis</i> is worsening the global threat of tuberculosis (TB). There is a need and urgency for the development of new treatments for TB, for the management of drug resistant TB (MDR-TB) and for improved regimens against drug-susceptible TB, with the goal of reducing toxicity and length of therapy that will boost patience compliance. The paucity of new drugs is a major obstacle to design new regimens while host-directed therapies (HDTs) are emerging as a promising area of research and are opening new avenues to fight TB. In this review, we discuss examples of potentially promising strategies aimed at improving the host response to <i>M. tuberculosis</i>, and argue how a better understanding of TB pathogenesis, with the fine characterization of the immunological mediators involved, may pave the way for the design of new therapies, the identification of new drugs or the repurposing of some already in use for other diseases. We emphasize that any HDTs shall be included as adjunct therapy to the drug-combination regimens already in use for TB, with the goal to reduce tissue damage and immunopathology and enhance bacterial clearance. We anticipate that the benefits of HDTs against TB will be highest against MDR-TB, where the activity of current regimens is poor and the cost high.