Abstract : Tuberculosis continues to be a major global health concern with over nine million new cases added annually and two million deaths every year. The emergence of multiple and total drug resistant strains of Mycobacterium tuberculosis has resulted in worldwide efforts to combat the disease using a variety of strategies. I will describe some of the efforts worldwide and our own to understand the pathogen and exploit the knowledge to develop vaccines and inhibitors targeted to the dreaded pathogen. The DNA within the cell is subjected to supercoiling (both underwinding and over winding of the two intertwined strands) and compaction. A dedicated bunch of enzymes known as topoisomerases catalyse the supercoiling, required during the genome duplication or when genes are expressed. Understanding how these molecular machines function in mycobacteria has been a major topic of our study. These enzymes are attractive targets for lead molecule development. In addition, we are also studying nucleoid associated proteins(NAPs) of mycobacteria. These are DNA binding proteins that participate in topology modulation by organizing the genome into a more compact form without involving enzymatic reactions.We have used a combination of approaches- genetics, molecular and cell biology as well as structural probing to study the function of these essential proteins in mycobacteria. To understand their cellular role, and to target them, we have either developed inhibitors or constructed knock down strains to down regulate their expression and disturb cellular function. These topology perturbation studies (both genetic and chemical) would reveal hidden secrets of the pathogen to facilitate better intervention strategies.