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With increasing drug pressure,\u00a0<jats:italic>Mycobacterium\u00a0tuberculosis<\/jats:italic> (<jats:italic>Mtb<\/jats:italic>) activates various pathways to counter drug\u2010related toxicity. Signaling modules steer the evolution of\u00a0<jats:italic>Mtb<\/jats:italic>\u00a0to a variant that can survive, persist, adapt, and emerge as a form that is resistant to one or more drugs. Recent studies reveal that about 1\/3rd of the annotated\u00a0<jats:italic>Mtb<\/jats:italic>\u00a0proteome is modified post\u2010translationally, with a large number of these proteins being essential for mycobacterial survival. Post\u2010translational modifications (PTMs) such as phosphorylation, acetylation, and pupylation play a salient role in mycobacterial virulence, pathogenesis, and metabolism. The role of many other PTMs is still emerging. Understanding the signaling pathways and PTMs may assist clinical strategies and drug development for\u00a0<jats:italic>Mtb<\/jats:italic>. In this review, we explore the contribution of PTMs to mycobacterial physiology, describe the related cellular processes, and discuss how these processes are linked to drug resistance. 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