Tuberculosis (TB) is one of the oldest and most-deadly human diseases. The main etiological agent, Mycobacterium tuberculosis, caused approximately 10.4 million new infections and 1.6 million deaths in 2016. The World Health Organization estimates that 1/3 of the world population harbors a latent TB infection. This pathogen can survive asymptomatically in the host for decades, but the extent of its metabolic activity during such latent infections is unclear. To respire and metabolize in host cells, M. tuberculosis must acquire essential metals and acquire or synthesize enzyme cofactors. Herein we explore control of the copper-acquisition sigma factor, SigC, by copper. We also interrogate genes predicted to function in the synthesis of co-enzyme B12 (Co-B12) in M. tuberculosis. Copper is a cofactor of electron-transfer enzymes, including a Zn/Cu-dependent superoxide dismutase, and a type a/a3 respiratory complex in M. tuberculosis. Intracellular free copper levels are nearly undetectable; therefore, pathogenic bacteria have evolved mechanisms to scavenge this essential metal. The sigC gene enables growth in copper-starved medium and upregulates expression of ctpB and the PPE1-nrp operon. Here, we demonstrate sigC is absolutely required for growth in copper-chelated medium and that copper destabilizes SigC in M. tuberculosis. This supports a model in which SigC is post-translationally regulated by copper levels. In M. tuberculosis, Co-B12 functions in methionine synthesis, fatty-acid metabolism, and ribonucleotide reduction. To understand the role of Co-B12 in M. tuberculosis, we assessed predicted Co-B12 biosynthetic genes from M. tuberculosis in Salmonella Typhimurium Co-B12 synthesis pathway mutants. Results indicate that 16 genes functionally complement late-cobalt insertion specific Co-B12 biosynthetic genes from S. Typhimurium. These data suggest that M. tuberculosis may synthesize Co-B12 in low oxygen environments in its host. Hypoxic in vitro cultivation of M. tuberculosis did not result in detectable Co-B12 synthesis, suggesting that other signals or factors may be required. This body of work expands the knowledge base of mechanisms for survival and metabolism by M. tuberculosis, and informs future research to target critical components in the development of effective antibiotics and vaccines.