During infection, Mycobacterium tuberculosis is exposed to a diverse array of microenvironments in the human host, each with its own unique set of redox conditions. Imbalances in the redox environment of the bacillus or the host environment serve as stimuli, which could regulate virulence. The ability of M. tuberculosis to evade the host immune response and cause disease is largely owing to the capacity of the mycobacterium to sense changes in its environment, such as host-generated gases, carbon sources, and pathological conditions, and alter its metabolism and redox balance accordingly for survival. In this article we discuss the redox sensors that are, to date, known to be present in M. tuberculosis, such as the Dos dormancy regulon, WhiB family, anti-s factors, and MosR, in addition to the strategies present in the bacillus to neutralize free radicals, such as superoxide dismutases, catalase-peroxidase, thioredoxins, and methionine sulfoxide reductases, among others. M. tuberculosis is peculiar in that it appears to have a hierarchy of redox buffers, namely, mycothiol and ergothioneine. We discuss the current knowledge of their biosynthesis, function, and regulation. Ergothioneine is still an enigma, although it appears to have distinct and overlapping functions with mycothiol, which enable it to protect against a wide range of toxic metabolites and free radicals generated by the host. Developing approaches to quantify the intracellular redox status of the mycobacterium will enable us to determine how the redox balance is altered in response to signals and environments that mimic those encountered in the host.