The global tuberculosis (TB) control effort is focused on interrupting transmission of the causative agent, Mycobacterium tuberculosis, through chemotherapeutic intervention in active infectious disease. The insufficiency of this approach is manifest in the inexorable annual increase in TB infection and mortality rates and the emergence of multidrug-resistant isolates. Critically, the limited efficacy of the current frontline anti-TB drug combination suggests that heterogeneity of host and bacillary physiologies might impair drug activity. This review explores the possibility that strategies enabling adaptation of M. tuberculosis to hostile in vivo conditions might contribute to the subversion of anti-TB chemotherapy. In particular, evidence that infecting bacilli are exposed to environmental and host immune-mediated DNA-damaging insults suggests a role for error-prone DNA repair synthesis in the generation of chromosomally encoded antibiotic resistance mutations. The failure of frontline anti-TB drugs to sterilize a population of susceptible bacilli is independent of genetic resistance, however, and instead implies the operation of alternative tolerance mechanisms. Specifically, it is proposed that the emergence of persister subpopulations might depend on the switch to an altered metabolic state mediated by the stringent response alarmone, (p)ppGpp, possibly involving some or all of the many toxin-antitoxin modules identified in the M. tuberculosis genome.