Improved treatments are needed for nearly all forms of Mycobacterium tuberculosis infection. Adjunctive host-directed therapies have the potential to shorten tuberculosis treatment duration, prevent resistance and reduce lung injury by promoting autophagy, antimicrobial peptide production and other macrophage effector mechanisms, as well as by modifying specific mechanisms that cause lung inflammation and matrix destruction. The range of candidates is broad, including several agents approved for other clinical indications that are ready for evaluation in Phase II clinical trials. The promise of new and existing host-directed therapies that could accelerate response and improve tuberculosis treatment outcomes is discussed in this Opinion article.