The ability of Mycobacterium tuberculosis (Mtb) to persist in the presence of anti-mycobacterial drugs and immune effector functions is the greatest obstacle in our attempt to eradicate tuberculosis (TB). My laboratory is investigating the hypothesis that persistence is enabled by entrance into and maintenance of a physiological state that is metabolically distinct from that of actively replicating bacilli. The aim of this work is to define this state (or series of states) and characterize pathways that are essential for its establishment and maintenance. My laboratory uses a variety of classical and novel approaches in mycobacterial genetics, biochemistry, physiology, and metabolomics to characterize i) novel aspects of intermediary metabolism in Mtb, ii) metabolic requirements for phenotypic drug tolerance, and iii) drug targets and drug-like compounds effective against persistent bacilli. While these studies address basic science questions about unique aspects of Mtb, they will also provide important contributions to the collaborative and global effort to eradicate TB.