© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. Tuberculosis remains a global emergency causing an estimated 1.5 million deaths annually. For several decades the major focus of tuberculosis treatment has been on antibiotic development targeting Mycobacterium tuberculosis. The lengthy tuberculosis treatment duration and poor treatment outcomes associated with multi-drug resistant tuberculosis (MDR-TB) are of major concern. The sparse new tuberculosis drug pipeline and widespread emergence of MDR-TB signal an urgent need for more innovative interventions to improve treatment outcomes. Building on the historical Pasteur-Bechamp debates on the role of the "microbe" vs the "host internal milieu" in disease causation, we make the case for parallel investments into host-directed therapies (HDTs). A range of potential HDTs are now available which require evaluation in randomized controlled clinical trials as adjunct therapies for shortening the duration of tuberculosis therapy and improving treatment outcomes for drug-susceptible tuberculosis and MDR-TB. Funder initiatives that may enable further research into HDTs are described.