Mycobacterium tuberculosis is an incredibly successful pathogen with an extraordinary penetrance of its target host population. The ability to infect many yet cause disease in few is undoubtedly central to this success. This ability relies on sensing and responding to the changing environments encountered during the course of disease in the human host. This chapter discusses these environmental cues and stresses, and explores how the genome of Mtb has evolved under the purifying selections that they exert. In analyzing the response of Mtb to a broad range of intracellular pressures it is clear that, despite genome down-sizing, Mtb has retained an extraordinary flexibility in central carbon metabolism. We believe that it is this metabolic plasticity, more than any of the virulence factors, that is the foundation for Mtb's qualities of endurance.