Tuberculosis is a major global health challenge and is far from being controlled. Development of resistance to currently available drugs due to the successful adaptation of the pathogen has been a major contributing factor for its control failure. Presently, there is an immense interest in identification of pathways, unique to the intracellular environment that could be utilized for the development of new and better drugs. In this sequence, targeting essential functions of Mycobacterium tuberculosis has emerged as a reliable strategy for containing the spread of the disease by this organism. The fact that iron has been known to be the key player required for its survival and ability to spread infection, the organism must carefully balance iron acquisition with iron uptake for its infectivity. Conversely, this iron homeostatic process could be disrupted to interfere with the survival and replication of this bacterium in host. Urgency to develop such an approach has been further strengthened with the worldwide recrudescence of tuberculosis especially in the developing nations of the world. In the current review, we have focused on the recent developments in targeting the essential functions of mycobacterium especially interfering in its iron homeostatic process. The relevance of iron for mycobacterial virulence, the intracellular survival and the immense potential of targeting iron-sulfur (Fe-S) cluster containing proteins in tuberculosis drug discovery has been discussed.