ABSTRACT Accumulating evidence has left little doubt about the importance of persistence or metabolism in the biology and chemotherapy of tuberculosis. However, knowledge of the intersection between these two factors has only recently begun to emerge. Here, we provide a focused review of metabolic characteristics associated with Mycobacterium tuberculosis persistence. We focus on metabolism because it is the biochemical foundation of all physiologic processes and a distinguishing hallmark of M. tuberculosis physiology and pathogenicity. In addition, it serves as the chemical interface between host and pathogen. Existing knowledge, however, derives largely from physiologic contexts in which replication is the primary biochemical objective. The goal of this review is to reframe current knowledge of M. tuberculosis metabolism in the context of persistence, where quiescence is often a key distinguishing characteristic. Such a perspective may help ongoing efforts to develop more efficient cures and inform on novel strategies to break the cycle of transmission sustaining the pandemic.