Mycobacterium tuberculosis (M. tb) the causative agent of tuberculosis (TB) causes 1.7 million deaths annually. According to the World Health Organization, in some areas of the world, 25% of TB cases are due to multi- or extensively drug resistant M. tb strains. In 2008, it was estimated that 440,000 individuals worldwide had contracted multi-drug-resistant TB with a 30% mortality rate (http://www.who.int/en/). These appalling statistics highlight the urgent need for new drugs to treat TB. Here, we propose an alternative way to fight M. tb infection by targeting key protein secretion systems required for virulence. With such an approach, rather than killing bacteria, as is the case with most antibiotics, the pathogen's ability to cause disease is diminished allowing its elimination by the immune system. We specifically focus on the specialised ESX-1 type VII secretion system (T7SS), the major and most studied virulence mechanism in M. tb (Fig. 1) that represents a new avenue for anti-TB drug development.