Granuloma formation represents a pivotal point during human infection with Mycobacterium tuberculosis, for this structure may limit mycobacterial spread and prevent active disease, while at the same time allow for the survival and persistence of viable mycobacteria within the host. The current therapeutic regimens for treating tuberculosis disease have proven effective in developing countries. However, in countries with large populations, limited access to health care, and high incidence of HIV co-infection, tuberculosis disease continues to represent a major global health emergency. Particularly, the emergence of extensively and multi-drug-resistant forms of tuberculosis underscores the need develop new treatment strategies. Recent mechanistic studies have identified bacterial virulence mechanisms that subvert host responses and lead to an inappropriate upregulation of host factors such as tumour necrosis factor-alpha (TNF-alpha) and matrix metalloproteinases (MMPs). Paradoxically, then, part of the mycobacterial virulence programme may be to promote granuloma development and maturation. These observations suggest that together with appropriate anti-microbials host-based therapeutics directed at TNF-alpha and MMP inhibition may counteract the microbial subterfuge, reduce the pro-granulomatous response, and offer an enhanced therapeutic effect. Host-directed therapy that alters the immune response may offer an alternative approach towards reducing treatment duration, the risk of anti-microbial resistance and improving patient outcome.