Leprosy serum reactive clone 2 (Lsr2; Rv3597c) is a recently identified nucleoid-associated protein that acts as a global transcriptional regulator of Mycobacterium tuberculosis. Strikingly, Lsr2 appears to play a critical role in controlling the expression of virulence-associated genes. Here the authors outline the current knowledge concerning this novel global regulator and its potential as a target for chemotherapeutic intervention. Compounds that induce high level expression of lsr2 may lead to abolishment of virulence traits and render the bacterium incapable of causing infection and/or disease. Alternatively, compounds that either silence lsr2 expression or block the protein's function could be lethal since it has been postulated that lsr2 is essential in M. tuberculosis.