Mycobacterium tuberculosis produces two main thiols; mycothiol (MSH) and ergothioneine (EGT). We identified the complete set of genes that code for both agents. We showed that MSH is used as an innate protectant against xenobiotics. MSH provides mycobacteria with the ability to resist host defense mechanisms, free radicals, alkylating agents, and antibiotics and activation of drugs against TB. Our studies of EGT revealed its role in nutrient-starved models of persistence and long-term infection of macrophages. We further showed that central carbon metabolism, protein kinases and lipid precursors regulate EGT production and that EGT, like MSH, modulates drug sensitivity. Current students focus on generating conditional mutants that will enable us to better understand the roles of thiols in the physiology of Mycobacterium tuberculosis.