Redox homeostasis and stress responses due to environmental changes is a broad and rapidly expanding field. For pathogenic bacteria, such defenses play pivotal roles in protecting the pathogen through metabolic modification of the bacterium, reversible protein oxidation, neutralization of reactive oxygen or nitrogen species, modulation of host responses, and processing of xenobiotic compounds. The defense mechanisms employed by Mycobacterium tuberculosis, the bacterium synonymous with the disease, must account for growth environment variation that includes extracellular survival prior to phagocytosis, growth inside a macrophage, division following macrophage escape, maintenance of long-term infection in a granuloma, and transition to reactivation. The described studies take a protein structure-based look at both Mycothiol utilization and Ergothioneine production to enhance the understanding of some of these defenses and afford the development of compounds that may modulate or inhibit these responses as a basis for enhancing drug current therapies.