In this paper, we review the evidence supporting the notion that the genome of Mycobacterium tuberculosis sustains considerable damage as a result of exposure to nitrosative and oxidative stress. On these grounds, we propose a model in which stress-induced DNA damage in M. tuberculosis plays a role in the evolution of chromosomally encoded drug resistance mutations by altering the global mutation rate by mechanisms akin to SOS mutagenesis. Finally we review some of the factors determining the evolution of PE/PPE and MIRU (There are many abbreviations in this paper which are not defined, e.g. SOS, PE/PPE and MIRU. Please indicate whether these are well known and will be understood by readers or whether they should be defined at first mention) loci whose sequence characteristics are suggestive of their classification as heritable local mutators.