Metabolism is a widely recognized facet of all host-pathogen interactions. Knowledge of its roles in pathogenesis, however, remains comparatively incomplete. Existing studies have emphasized metabolism as a cell autonomous property of pathogens used to fuel replication in a quantitative, rather than qualitatively specific, manner. For Mycobacterium tuberculosis, however, matters could not be more different. M. tuberculosis is a chronic facultative intracellular pathogen that resides in humans as its only known host. Within humans, M. tuberculosis resides chiefly within the macrophage phagosome, the cell type, and compartment most committed to its eradication. M. tuberculosis has thus evolved its metabolic network to both maintain and propagate its survival as a species within a single host. The specific ways in which its metabolic network serves these distinct, through interdependent, functions, however, remain incompletely defined. Here, we review existing knowledge of the M. tuberculosis-host interaction, highlighting the distinct phases of its natural life cycle and the diverse microenvironments encountered therein.